Page 1 of 168 Block I: Homeostasis & Excitable Cellstmedweb.tulane.edu/clubs/owlclub/wp-content/...a.Hypertonic is anything >290mMol/kg b. Hypotonic is anything < 290 mMol/kg

Brown, Eriksen, Jones, Heffernan, Kanjanavaikoon, Leo, Mishkin, Stern, Verlander &Wasserman Ed. Mishkin 2006

Page 1 of 168

Block I: Homeostasis & Excitable Cells Body Fluids and Compartments I: Functional Organization of the Body and Homeostasis

1. Explain homeostasis: a. The set of coordinate physical processes that maintain steady state b. includes adjustments to stress and environmental change

2. Define health: a. How well we can cope with the environment and maintain optimum function b. lack of health is reflected by an inability to maintain homeostasis during

environmental change 3. Levels of organization & importance:

a. Cell: i. signal transduction, metabolism, membrane transport, channels ii. pathology example: cardiac myopathy

b. Tissue: i. single type of cell maintaining proper function ii. pathology – cancer

c. Organ i. groups of organs operating in a coordinated manner ii. pathology – congestive heart failure

d. Organism i. groups of cell systems communicating with each other ii. pathology – high bp or obesity

4. Basic elements of physiological regulation and feedback control a. Disturbance sensor has a receptor mechanism transducer receives

information and processes it decoder effector response return to normal feedback tells sensosr whether desired result has been achieved

b. Feedback: i. positive: accentuates disturbance –

1. childbirth 2. orgasm

ii. negative: returns critical variable to normal (very common) iii. feedback controller:

1. sends forcing functions to controlled system iv. adaptive controller

1. slower and evaluates measures of performance v. feedforward

1. A B C D and A k, which is the enzyme that catalyzes [C D]

5. Not in the LOs, but useful: a. Steady state error is the amount that the final is off after compensation b. Gain = Amount of compensation/steady state error c. More gain mark of efficiency

6. More information from the study questions: a. Claude Bernard – Father of modern physiology, first distinguished between the

external environment and the internal milieu b. Walter Cannon – Emphasized role of maintaining homeostasis in order to maintain

a favorable internal environment Body Fluid Components and Fat


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1. Basic composition of the body (lean mass, total body water & its distribution, adipose)

a. Ideally kg % weight % volume Total body weight 70 100 Lean body mass 55 79 Total body water 40 57 100 Inter-cellular fluid 25 36 63 Extra-cellular fluid 15 21 37 Interstitial fluid 11.5 16 28 Plasma fluid 3.5 5 9

b. Water distribution: i. Total body water, TBW = 73% of LBM

ii. Extracellular water, ECFV = 1/3 TBW 1. includes interstitium and plasma

iii. Intracellular water, ICFV = 2/3 TBW 2. Calculating obesity based on body water

a. TBW = 73% LBM i. use TBW to calculate LBM

b. LBM is ideally 79% of total weight i. use LBM to calculate ideal weight

c. Compare ideal weight to actual weight d. Actual weight – LBM = pounds of fat e. pounds of fat / total weight = % fat f. If the % fat is higher than 21 – degree of obesity is how far over 21% it is

3. Normal ion concentrations in fluid compartments (be able to convert between molar and mass values )

Total osmolality of both plasma and cell water is 290 mMol/kg. To convert between mols and mass, divide by molecular weight.

4. Tonicity and predicting fluid exchange a. Hypertonic is anything >290mMol/kg b. Hypotonic is anything < 290 mMol/kg c. Isotonic = 290 mMol/kg d. Water will move in the direction of higher osmolality. Fluid exchange across

a membrane is based on total solute concentration (osmolality) with only the total amount of impermeable solutes being taken into consideration.

e. Therefore hypertonic solutions gain water, hypotonic solutions lose water, and isotonic solutions have no net change in water

f. Ways of looking at particles in solution: i. Valence – Charge on particles mEq

ii. Osmolarity = total # particles in solution iii. Osmolality = total # particles in water per weight iv. molarity = moles/L v. osmolarity = osmols/L

Cations Plasma mMol/L Cell Water mMol/kg Na+ 135-145 10-14 K+ 3.6-5.2 120-145 Anions Cl- 96-107 5-10 HCO3 22-28 <10


Page 3 of 168 vi. osmolality = osmols/kg

vii. osmolairty = osmolality for body fluids because 1 L of water is 1 kg viii. osmoles are the number of particles in solution regardless of charge or MW

1. multiply molarity by the # of particles that each molecule dissociates into in solution

ix. equivalents: one electrochemical equivalent is the amount of an ion that will combine with 1 M of a univalent ion of the opposite persuasion (cation or anion)

x. The concentration of a solute in mEQ/L is the concentration of the solute in (mmol/L) X valence

g. Infusions: i. Isotonic infusion:

1. ↑ECFV by amount infused 2. no change in ICFV

ii. Hypertonic infusion 1. ↑ ECFV by amount infused + the amount of water that comes out

to dilute the solute 2. ↓ ICFV

iii. Hypotonic infusion: 1. ↑ ECFV by amount infused - the amount of water that goes into

the cells to equilibrate the ECFV 2. ↑ ICFV

5. Indicator dilution principle to determine plasma volume, ECFV, TBW a. Principle: an unknown volume can be determined by administering an indicator

substance which distributes itself in a known component of body fluid and waiting for equilibration, then measuring the concentration of the indicator

b. Indicators and body compartments i. TBW -- must be a substance that will diffuse freely throughout

ii. ECFV -- must be a substance that can’t get into cells iii. Plasma volume -- must be a substance that can’t get into RBCs or out of

the capillary once injected Indicator Substances to measure various compartments TBW ECV BV PV Heavy water (D2O) Inulin Labeled Fe RISA HTO Mannitol Cr51 T-1824 (Evan’s Blue) Labeled Na Labeled SO4

c. Math: i. Volume = amount of indicator/indicator concentration.

ii. You get an initial volume of indicator and concentration, and a final concentration. It’s just a ratio; the total amount of indicator didn’t change, the total volume did, so you can set up a proportion and do the math for TBW, ECFV, and/or plasma volume

iii. ICFV, blood volume and interstitial fluid can be calculated from these values

1. Blood volume = plasma volume/(1-Hc) 2. ICV = TBW – ECV 3. Interstitial volume = ECV – PV

Body Fluid Volumes (ideal)


Page 4 of 168 Kg % weight % volume Total body weight 70 100 Lean body mass 55 79 Total body water 40 57 100 Inter-cellular fluid 25 36 63 Extra-cellular fluid 15 21 37 Interstitial fluid 11.5 16 28 Plasma fluid 3.5 5 9 Membranes and Transport I: Diffusion and Osmosis

1. Fick: Electro-chemical gradient, diffusion coefficient, surface area, temperature a. Fick’s first law: J= -DAΔC/Δx b. Translation:

i. J is flux (net rate of diffusion over time) ii. D is diffusion coefficient (particular to a solute)

iii. A is the surface area of the membrane iv. ΔC is the concentration gradient v. ΔX is membrane thickness

c. For uncharged particles only 2. Time, diffusion, distance

a. 1 µm = 0.5 msec b. 10 µm = 50 msec c. 100 µm = 5 sec d. 1000 µm = 8.3 min – kinda stops being worth it after that

3. Lipid solubility and membrane permeability a. Lipid bilayer is the major barrier to permeation by solutes b. Lipids can traverse membranes c. The amount of lipid solubility in a solute is the oil-water partition coefficient, β. To

find this, they create a half water, half lipid solvent and see how much of the solute winds up in the lipid portion – this amount is the β, which is directly proportional to Kp, the permeability constant of that solute for that membrane

i. higher Kp, higher β, more diffusion ii. Kp = βDm/Δx

1. Dm is the diffusion coefficient of the membrane d. Electrical gradient and molecular size also effect diffusion

4. Molecular size and diffusion a. molecular size plays a role in membrane diffusion

i. smaller molecules diffuse more easily b. in aqueous solution, diffusion is affected by

i. the solubility in water ii. charge iii. size was listed but it has less effect in solution than through a membrane

5. Permeability coefficient and flux a. J = Kp (Co-Ci) b. Flux = permeability constant (concentration gradient)

6. Van’t Hoff equation: physical and chemical influences on osmotic pressure a. Van’t Hoff is for osmotically active solute particles b. Π = RT (Φ i c)


Page 5 of 168 c. Translation: osmotic pressure = gas constant X absolute temperature X osmotic

coefficient X the number of ions formed by dissociation of the solute X concentration of the solute

i. R is the gas constant ii. T is the absolute temperature iii. Φ is the osmotic coefficient iv. i is the number of ions formed by dissociation of solute molecule v. c is the concentration of solute (mols/L)

d. Increasing concentration of solute and an increasing number of ions on dissociation result in increased osmotic pressure.

7. Relationship between movements of osmotically active particles and water a. Osmotically active particles cannot diffuse through membranes b. Water will move from lower to higher concentrations of these particles until

compartments are equilibrated 8. Molarity, osmolarity, tonicity – and effects on cells in solution

a. Molarity = moles/liter b. osmolarity = ions/liter c. tonicity = impermeable ions/liter

i. Tonicity is the only one that causes net water movement 9. Reflection coefficient

a. Reflection coefficient, σ, is a measure of relative permeability b. σ= 1 – (Cfiltrate/Csolution)

i. Cf = [solute] in filtrate after pushing all the water through the membrane with a piston.

ii. Cs = [solute] in original solution at T=0 c. 0 < σ < 1

i. 0 is completely reflected, not permeable at all ii. 1 is completely permeable, not reflected at all

d. This is important for understanding and predicting effecitve osmotic pressure difference across a membrane, taking into account potential movements of water and solute

10. Filtration coefficient – hydraulic conductivity a. Filtration coefficient measures relative permeability of water through a membrane b. Relates J of water across a membrane to the hydrostatic pressure and effective

osmolarity (oncotic pressure) which determine water diffusion c. Formulas, values, constants

i. Vw = Kf (∆P) ii. Vw = Kf(∆πeff) iii. Vw = Kf (∆πeff - ∆P) iv. ∆πeff = σRT(Cin – Cout) v. Vw = Volume of water crossing membrane vi. Kf = filtration coefficient vii. ∆πeff = effective osmotic pressure difference across membrane viii. ∆P = hydrostatic pressure difference across membrane

1. = reflection coefficient ix. R = gas constant x. T = Absolute temperature xi. C = concentration of solute (mol/L)


Page 6 of 168 Membranes and Transport II: Carrier-Mediated Transport

1. Carrier-mediated transport systems

a. Facilitated diffusion: i. carrier-mediated

ii. only goes high concentration to low concentration b. Active transport

i. carrier-mediated ii. can go against concentration gradient

c. subtypes i. primary: directly dependent on ATP

ii. secondary: coupled to another transport event, where a molecule is going down its concentration gradient

1. cotransport (both go the same way) 2. antiport (swap ions)

d. All carrier mediated transport is faster than diffusion e. Carrier proteins are highly specific (chemically and sterically) f. Transport can be inhibited compeititvely or non-competitively

2. Examples of diffusion mechanisms a. Diffusion

i. oxygen, carbon dioxide, water, small polar molecules b. Facilitated diffusion

i. glucose c. Primary Active

i. Na/K pump d. Secondary Active

i. Ca2+ and H+ trasnported by Na+ 3. Na+/K+ pump – actions, regulation, relevance

a. Uses an ATPase to transport 3 Na+ out of the cell and 2 K+ in b. Rate of transport varies with both concentration gradients c. high K+ is maintained inside cell d. high Na+ is maintained outside cell e. maintains membrane potential f. powers other pumps by providing gradient

i. can regulate water concentrations 4. Na+/K+ pump maintaing cell volume under normal conditions

a. Na+/K+ pump counteracts (rectifies) the passive diffusion of each ion across the membrane down its electrochemical gradient

b. Na+/K+ pump can help regulate water concentrations 5. Role of membrane transport and channels in regulatory volume response to hypo and

hyperosmotic extracellular solutions a. Water moves in or out stretches or shrinks cell activates specific channels and

active transport b. Hypoosmotic cell pumps out solute (esp K+Cl-) water goes towards solute

water won’t flood the cell i. Transport mechanisms:

1. K+ channels open, Cl- follows K+ through its own channel 2. cotransport of K+ and Cl – 3. K+H+ exchange and Cl-/HCO3- exchange

c. Hyperosomotic cell increases concentration of solute via Na/K/2Cl cotransport and organic osmolytes water follows ions water won’t all leave cell


Page 7 of 168 6. Structural properties of epithelial cells and specialized function

a. microvilli i. increased surface area for transport (absorption and secretion)

b. tight junctions i. join epithelial cells on their sides to prevent mixing of apical/basolateral

membrane proteins and extracellular compartments ii. create higher selectivity of what ions can pass through

c. functional syncytium i. free communication – like in cardiac muscle

d. apical membranes and basolateral membranes i. asymmetric distribution of membrane channels and transporters between

apical (absorption) and basolateral (secretion) membranes is essential for directionality of transport (aka vectorial movement)

e. paracellular pathways i. exist between leaky epithelial cells

ii. allow transport in between so that ions don’t have to actually cross into the cell to get through

7. Characteristics of epithelia a. leaky

i. allow paracellular pathways ii. prevent cellular swelling

iii. examples: 1. proximal renal tubules 2. small intestine

b. tight epithelia i. no paracellular transport

ii. examples 1. renal collecting duct 2. salivary gland duct

c. secretory i. moves materials from blood to lumen

d. absorptive i. move materials from lumen to blood

8. Specific and directional transport of solutes a. There is usually some kind of balance of apical and basolateral channels and pumps,

so that ions are able to go from the lumen, through the cell and into the blood – or in the other direction.

b. Na+/K+ pumps work faster than any of the other symports or antiports, so the concentrations of these ions can almost always be used to run other channels

c. example: sugars i. SGLT1 cotransports glucose and fructose through the apical membrane

1. 2 Na+ come in per 1 glucose ii. GLUT 2 transports glucose through the basolateral membrane iii. Na/K pumps on basolateral membrane Na from SGLT1 is pumped out

of the cell continued directional transport of glucose from the lumen, through the cell and into the blood

Physiology of Excitable Cells I


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1. Factors underlying electrical current flow a. Current is thought of from the point of view of ions in solution b. At rest, all cells have a membrane potential that is negative, meaning that the inside

of the cell is more negative than the outside c. concentration gradients for different ions vary considerably inside and outside the

cell i. outside – mostly sodium and chloride

ii. inside -- mostly potassium and anionic proteins (Pr-) iii. membrane is somewhat permeable to ions, not permeable to Pr-

2. Nernst equation a. Eion = ( RT ) * ln( [I+]o ) = -60log( [I+]o )

ZF [I+]i [I+]i

b. Translation: i. Eion = electrochemical transmembrane potential difference of the ion

ii. Z = charge of the ion iii. F = Faraday’s # iv. the last item shows the natural log of the ratio of the concentration of the

ion outside (o) and inside (i) the cell c. Nernst describes the diffusion potential generated by a single ion species – it

represents the transmembrane potential at which the electrical force will exactly balance with the concentration difference

d. Nernst only applies to a single ion species – the GHK equation (below) calculates the Em, for the entire membrane, based on the contributions of various ions

e. Nernst does not take into account relative permeabilities of the cell membrane to various ions – this limitation is also addressed by GHK

3. GHK’s important determinants of transmembrane potential a. inside/outside concentration of each species b. relative permeability to each species

4. How various cells can have different potentials despite identical gradients a. each ion has a different permeability in different membranes b. amount of permeability determines how much that ion’s Eion contributes to the

overall Em 5. Estimating quantity of ions that must move across the cell membrane to establish a

diffusion potential (Nernst potential) a. very few ions have to diffuse to produce a separation of charge change in the

membrane b. no discernable concentration change has to occur for there to be an appreciable

voltage across the membrane 6. Na/K pump and transmembrane potentials

a. K+ leaks out of cells and Na+ leaks in b. Over time, without the pump, ICFV and ECFV concentrations of these ions would

change 7. Depolarization and hyperpolarization

a. A polarized membrane is one where a separation of charge exists across it b. We look at polarity from the cell’s point of view c. At rest, membranes are polarized d. Resting Em is negative e. Ion movements that make the Em less negative are depolarizations

i. i.e., less polarized ii. still called depolarization if it hits 0 and becomes positive


Page 9 of 168 f. Ion movements that make the Em more negative are hyperpolarizations

i. i.e., even more polarized 8. Effects of passing current across the cell membrane

a. Place microelectrode in cell pass current b. In one direction, positive charges are injected into the cell – cell will become less

negative – depolarization c. In the opposite direction, negative charges are injected into the cell –

hyperpolarization d. enough stimulation can help the cell reach its threshold – producing an action

potential Physiology of Excitable Cells II

1. Passive electrical responses of cell membranes a. Currents applied to the membrane response of graded, proportional amplitude in

the same direction as the current b. Exponential decay as the potentials travel away from the site of stimulation

2. Excitable cells a. Cells that exhibit large, rapid changes in transmembrane potential in response to

sufficient depolarization -- Triggered changes = “action potentials” i. Neurons ii. Skeletal muscle iii. cardiac muscle iv. smooth muscle

b. Main requirement is sufficient voltage-gated sodium and/or calcium channels in the membrane

3. Threshold a. threshold is the membrane potential at which depolarization is sufficient to trigger a

Hodgkin cycle (i.e., which allows an action potential), a regenerative increase in membrane conductance to sodium ions

b. NOT static in a given cell – conditions can change the threshold 4. Passive electrical responses, local responses, and action potentials

a. Passive: i. initiated by subthreshold depolarization/hyperpolarization ii. graded iii. degrade

b. Local: i. slightly greater depolarization, resulting from a local increase in the

membrane conduction to sodium c. Action potential

i. binary ii. elicited by depolarization to at least threshold iii. depends on voltage-gated channels (not conduction of the membrane itself) iv. wave of permeability changes to sodium and then potassium v. amplitude is constant with distance vi. velocity is slower than a passive electrical response

5. Refractory periods & afterpotentials a. Refractory periods

i. The absolute refractory period is the period of time after an action potential when another action potential cannot be elicited, regardless of the strength of the stimulus

1. Na+ channels are largely inactivated


Page 10 of 168 ii. The relative refractory period follows the absolute refractory period and is a

period of time when it is more difficult than normal to elicit an action potential

1. some sodium channels are inactivated 2. membrane is hyperpolarized, making it harder to reach threshold

iii. refraction ensures that the action potentials being generated will move away from each other and travel in opposite directions, rather than colliding

iv. frequency of action potentials is limited b. afterpotentials

i. depolarizing or hyperpolarizing effects – can either increase or decrease excitability

ii. either effect can be present in an excitable cell 6. Mechanisms of action potential propagation, myelination, passive properties’

contributions a. Stimulus depolarization past threshold

i. increased permeability to sodium sodium rushes in more positive ions inside = large depolarization

ii. slightly delayed increased permeability to potassium potassium rushes out loss of positive ions = repolarization hyperpolarization/refractory period

b. Action potentials move in both directions from the point of initiation c. Myelin: increases velocity. Myelin sheath is an insulator with regular breaks

(“nodes”) that is resistant action potential jumps from node to node “saltatory conduction”

d. Unmyelinated areas act passively – signal is degraded 7. Axon diameter and myelination and velocity

a. Myelination increases velocity b. Larger axon diameters increase velocity

Physiology of Excitable Cells III

1. Increasing membrane permeability to an ion and changes in membrane potential a. Membrane potential moves towards the nernst potential for the ion to which the

membrane has been made more permeable 2. Ionic currents underlying each component of the action potential

a. Depolarization rapid increase in sodium permeability (gNa+) moves towards sodium nernst potential

b. Sodium in depolarization overshoot c. Potassium permeability increases Moves towards potassium nernst potential

Potassium out repolarization hyperpolarization d. Sodium channels inactivated absolute refractory period

3. Hodgkin cycle a. Sodium channel activation positive feedback cycle b. Activation of sodium channels increases gNa more sodium in more

depolarization more activationa of sodium channels c. This cycle allows action potentials

4. Membrane potentials’ effect on activation of voltage-gated sodium channels a. Na+ and K+ channels are activated by voltage

i. Na+ channels are also deactivated by voltage b. During maintained depolarization, sodium channels will be activated, but then they

will wind up in the refractory state – so the number of available channels will


Page 11 of 168 decrease and it will become more difficult to recruit enough channels to reach threshold thershold is elevated if this happens even more, further action potentials will be prevented -- “depolarizing blockade”

5. In/Activation of sodium, potassium, calcium conductances and action potentials a. Na+ activation Na+ influx action potential Na+ inactivation (responsible

for both absolute refractory and relative refractory periods) b. Potassium channels are activated and unactivated but not “inactivated” in the way

sodium channels are – activated state is open for potassium to rush out in the repolarization phase

6. Activation and inactivation of sodium channels and thrreshold a. Maintained depolarization more sodium channels in inactive/refractory state

harder to recruit channels to activated state threshold is increased 7. Gating properties of voltage-dependent ion channels, related to action potentials

a. Channels opening is binary (they’re either open or closed, all the way) b. When channels are open, the channel passes a pulse of current of constant

amplitude and varying duration -- frequency and duration is a function of the degree of depolarization and the calcium concentration

c. When membrane gates open or close, the electrical charge associated with them redistributes across the membrane changes membrane capacitance

d. Channels randomly open and close but depolarization and hyperpolarization respectively increase and decrease the chance channels will be open

8. Ionic mechanisms of action potentials of various shapes and durations a. Various excitable cells have action potentials of different shapes and durations,

depending on the particular pattern of permeability changes in the particular membrane

b. This will make way more sense in the cardio section Physiology of Excitable Cells IV

1. Changes in Em in action potentials and threshold that result from ECF ion changes a. External sodium changes:

i. At rest, little or no change – because the cell is far from the sodium nernst potential

ii. Decrease Sodium can’t flow in harder for an action potentials to be generated

iii. Increase More sodium flows in action potentials should happen more easily

b. External potassium changes: i. Resting membrane potential changes – because at rest, K+ is close to its

nernst potential, so Em will move towards Ek ii. Small increase enhance excitability iii. Permanent increase depolarization Na inactivation diminishes

excitability c. External calcium changes

i. Calcium can compete with sodium for sites in the sodium channels ii. Influx of calcium can lead to efflux of potassium can terminate bursts of

action potentials 2. Ion channels in a cell

a. Sodium b. Potassium c. Calcium


Page 12 of 168 d. Chloride

3. Membrane threshold and excitability during activation or inactivation – See #1 4. Na/K pump regulation of transmembrane gradients

a. Cell has action potentials sodium builds up inside, potassium is lost b. Na/K pump rectifies

5. Glia – we’re not responsible for this. Physiology of Excitable Cells V

1. Sizes and types of peripheral axons a. Peripheral nerve trunks contain both afferent and motor fibers

i. myelinated axons 1-20 μm diameter ii. unmyelinated axons 1 μm diameter (more common in a normal human

cutaneous nerve) iii. axon diameter is inversely proportional to conduction velocity

2. Two classification schemes of axons in nerve trunks a. myelinated vs. nonmyelinated b. axon diameter

3. Compound action potentials, generation, components, significance, uniqueness a. electrical measurement of whole nerve function b. composite of many axonal action potentials occuring simultaneously within the

nerve c. conducted along the nerve without any decrement in amplitude (like axonal ap) d. graded in amplitude as a function of intensity of stimulus (different from axonal ap) e. larger diameter axons have lower thresholds than smaller ones, so an increase in

stimulus recruits more axons by activating smaller ones 4. Records of compound action potentials and measurements

a. Stimuli (mild electrical shocks) are applied to the nerve through the skin with bipolar electrodes

b. Stimulus is placed at increasing distances from the proximal recording electrode on a hand muscle (at the thenar eminence)

c. Conduction time between stimulus and first deflection is measured d. Distance between stimulus and recording electrode is measured e. Difference between times at two locations and distances of the two locations is used

to estimate velocity 5. Compund action potentials’ clinical utility

a. Good for assessing general function, recovery of function after damage b. Only the largest myelinated fibers can be assessed in this way

i. No information about small fiber diseases c. small amplitude through skin

i. hard to measure 6. Injury and nerve conduction

a. Three main alterations i. Mild reduction in amplitude, normal latency ii. Normal amplitude, increased latency iii. Blocked response

b. Nerve compession injury delay c. Inured areas can have spontaneous action potentials

7. Spatial distribution of voltage-gaed ion channels a. Myelinated regions: K+ channels b. Unmyelinated nodes of ranvier: Na+ channels


Page 13 of 168 8. Mechanisms by which demyelination affects action potentials

a. Demyelination exposes regions of axonal membrane dense in K+ channels that cannot sustain action potentials slows or stops conduction of action potentials

Physiology of Excitable Cells VI: Synapses I and II

1. Impulse transmission sequence of events: a. Action potential propagates down axon depolarizes axon terminal opens

calcium channels influx of calcium release of transmitter substance neurotransmitter crosses synaptic cleft binds to receptors on postsynaptic membrane opens channels that nonselectively pass Na and K in depolarization EPSP or, if it reaches threshold action potential

b. NT effect is short-lived – NT is broken down or undergoes reuptake channels in postsynaptic membrane close Em slowly decays back to resting level

2. mEPPs, EPSPs, IPSPs a. mEPP: Mini end-plate potential. As you might have guessed from the name, this is

smaller than a regular EPP. They are generated at the muscle endplate by the spontaneous release of acetylcholine (ACh) from the presynaptic motoneuron axon terminal.

b. EPP or EPSP: Excitatory postsynaptic potential: a transmitter-induced change in Em equilibrium potential is above threshold always depolarizes

i. Summation of EPPs can lead to an action potential c. IPSP: Inhibitory postsynaptic potential: a transmitter-induced change in EM

equilibrium potential is below threshold almost always hyperpolarizes 3. Explanation for EPSP and IPSP action

a. See question 2 b. When the synapse becomes active, the Em approaches the equilibrium potential of

the signal – EPSP or IPSP c. IPSPs can be depolarizing if they result in the Em being clamped down at an Em

that is below threshold – increased membrane conductance underlying the IPSP contributes to this clamping by causing concurrent EPSPs to be attenuated.

d. IPSPs always have their Em below threshold 4. Mechanisms of presynaptic inhibition and facilitation

a. Presynaptic inhibition: i. a configuration of synaptic contacts that leads to a reduction in amount of

NT release upon stimulation 1. Open chloride channels hyperpolarization can’t reach

threshold 2. NT sustained partial depolarization inactivates Na channels

can’t reach threshold ii. Either way, the IPSP prevents the EPSP from reaching threshold

b. Facilitation: i. Accumulation of calcium in the nerve terminal can result in a greater NT

release ii. This is especially relevant in Eaton Lambert syndrome, an autoimmune

disease of calcium channels that causes weakness which improves with exercise. Calcium channels in this disease let less calcium through than in a normal synapse, and the improvement is a result of calcium build up over multiple action potentials, which eventually summate to produce increased response.

5. Temporal and spatial summation


Page 14 of 168 a. Temporal: when presynaptic action potentials (PSPs) from one stimulus occur close

together and are summed to generate a resulting Em b. Spatial: when PSPs from multiple stimuli at slightly different points on the soma or

dendrites are summed to generate an Em c. Summation bring Em above threshold action potentials d. IPSPs can summate with EPSPs to determine Em

6. Postsynaptic membrane a. Sensitivity of the postsynaptic membrane – unchanged by exposure to repetitive

stimulation i. proven because mEPPs are very consistent, regardless of recent action

potentials b. EPP amplitude declines to a plateau during a high frequency train of impulses c. Conclusion: there is less NT being released over time because of depletion of

substores i. one store contains immediately releasable NT ii. second store is less mobile and replenishes the first store

d. Role of the neuron in integrating inputs i. Synaptic potentials generated closer to the soma have the most effect ii. Axon hillock/initial segment has the lowest threshold for action potentials iii. Synapses on distal dendrites, though less sensitive than the soma, can

generate calcium-mediated dendritic spikes, generated at local trigger zones in the dendrites boost amplitude of remote synaptic potentials get message to soma generate action potentials

Muscle Physiology I and II: Skeletal Muscle

1. Macroscopic organization of skeletal muscle a. muscle fiber is surrounded by endomysium b. muscle bundle is surrounded by perimysium c. epimysium surrounds entire muscle d. endomysium + perimysium + epimysium = tendon

2. Microscopic organization of muscle fibers that form thick and thin filaments a. Muscle fibers are multinucleated b. nuclei just under plasma membrane c. light sections: thin filaments – actin d. dark sections: thick filaments – myosin e. organized into myofibrils with bundles of contractile proteins

i. each bundle has 1 thick filament surrounded by 6 thin f. myofibrils make up a muscle fiber

3. Sequence of molecular events underlying sliding filaments and crossbridge cycling a. Myosin proteins have heads (sticking out) and tails (part of thick filament). b. During contraction: ATP binds to myosin head head is released (rigor

configuration) ATP hydrolyzes energy released head “cocks” to resting position calcium binds troponin tropomyosin on thin filament moves actin binding sites exposed phosphate released from head head binds to globular actin ADP released head uncocks back to original position “power stroke” – it moves the filaments with it

4. Action potential Calcium release a. At neuromuscular junction (NMJ) AP starts propagates down plasma membrane

and into muscle cells along T-tubules where T-tubules contact the SR, depolarization configuration change in L-type calcium channels in the T-tubule


Page 15 of 168 membrane conformation change SR calcium-release channels open calcium goes into muscle cell cytoplasm binds troponin… see above

5. Non-contractile proteins & sarcomere length (titin) & muscle viability (dystrophin) a. Titin extends from the M-line to the Z-line and positions thick filaments so that

they can interact with thin filaments to provide elasticity to the sarcomere so that it expands to its starting position upon relaxation (like a spring) pushes Z-lines back to their initial positions have crossbridge cycling has stopped

b. Dystrophin helps transmit muscle force to surrounding connective tissue i. dystrophin is part of the costamere, which links Z-discs to the basal lamina ii. minimizes muscle damage due to eccentric muscle contraction (lengthening

contractions) in normal exercise iii. The malformation or lack of dystrophin is the cause of muscular dystrophy

(absence is Duchenne MD). 6. Costameres in transmitting force

a. Basal lamina forms connective tissues that come together to form the tendon b. Sarcomere shortens costamere transmits force from z-discs to basal lamina

7. Sequence of events coupling an action potential to a muscle contraction a. AP presynaptic terminal depolarization open calcium channels Ca2+ in

ACh storage vesicle release ACh crosses synaptic cleft binds to receptors in muscle membrane Na and K channels open Positive ion flux EPSP depolarize membrane to threshold At neuromuscular junction (NMJ) AP starts

propagates down plasma membrane and into muscle cells along T-tubules where T-tubules contact the SR, depolarization configuration change in L-type calcium channels in the T-tubule membrane conformation change SR calcium-release channels open calcium goes into muscle cell cytoplasm calcium binds troponin tropomyosin on thin filament moves actin binding sites exposed phosphate released from head head binds to globular actin ADP released power stroke

8. Three mechanisms that remove calcium from sarcoplasm a. Ca2+ ATPase pumps calcium against its gradient into ECF and back into SR b. Na+/Ca2+ exchanger uses Na+ gradient to pump 1 Ca+ out and 3 Na+ in

i. powered by Na/K pump 9. Three major biochemical pathways used by muscle to generate ATP

a. Transfer phosphate from creatine phosphate to ADP i. fastest ii. limited by supply of creatine phosphate

b. Anaerobic glycolysis i. can be used when there is no oxygen ii. faster than aerobic iii. 2ATP/glucose

c. Aerobic respiration i. slowest ii. most efficient: 36 ATP/glucose, 128 ATP/fatty acid

10. Isotonic and isometric muscle contractions a. Isotonic

i. generate force to move object ii. takes longer

b. Isometric: i. muscle length is fixed, shortening cannot occur ii. shorter latency period

11. Muscle length and force


Page 16 of 168 a. Amount of overlap between thick and thin filaments determines the possible force

that can be generated by a muscle b. When the muscle length is too short, filaments interfere with each other and thin

filaments are pulled in opposite directions, reducing the amount of force that can be generated

c. When the muscle length is too long, there is too little overlap, and maximum force is reduced

d. At 70-130% length, the generated force increases to its maximum. This one’s just right, said Goldilocks.

12. Force-velocity relationship and isometric point a. During an isotonic contraction, as the load increases, the maximum contraction

velocity decreases b. Isometric point: When load is equal to the maximum force that the muscle can

generate – so the muscle is contracting with zero velocity 13. Three different muscle fiber types and organization of motor units

a. Slow-resistant/slow-oxidative i. weakest, slowest contraction, use oxidative phosphorylation to generate

ATP, fatigue slowly b. fast-resistant

i. fast contraction velocity, use oxidative phosphorylation to generate ATP, intermediate rate of fatigue

c. fast-fatigable i. largest, fastest contractions, use glycolysis to generate ATP, fast fatigue

d. Motor unit = motor neuron + all of the fibers it contacts 14. Major mechanisms of neuronal induction of increased force

a. Increased action potential frequency summation stronger contractions b. Increase number of active motor units Increased number of recruited muscle

fibers increased force c. When only a few motor units are active, muscle contraction force is lower but

muscle contraction is still generally even throughout the muscle area 15. Muscular dystrophy, myasthenia gravis, myotonia and periodic paralysis

a. Muscular dystrophy i. No dystrophin progressive muscle degeneration

ii. X-linked heritability b. Myasthenia gravis

i. Antibody binds to Acetylcholine receptors (nAChRs) weakness c. Myotonia

i. mutations in skeletal muscle Cl- channel decrease membrane conductance

d. Periodic paralysis i. mutations in skeletal muscle Ca2+ channel OR mutations altering

inactivation in skeletal sodium channels decreases and increases in extracellular K+ can induce temporary muscle paralysis

Muscle Physiology III: Smooth Muscle

1. Differences between skeletal muscle fibers and smooth muscle fibers a. Smooth muscle

i. cells are small ii. single, central nucleus

iii. less densely packed contractile fibers iv. thick and thin filaments are not highly organized


Page 17 of 168 v. thick and thin filaments are arranged diagonally across the cell

vi. thin filaments connect at dense bodies instead of z-discs 2. Smooth muscle fiber linkage

a. gap junctions – electrical contacts forming ion channels spanning the membranes of two cells

b. structural junctions – can act as tissue instead of individual cells 3. Contraction of smooth muscle and phosphorylation’s role

a. Crossbridge cycling as in skeletal muscle b. Regulated at thick and thin filament levels:

i. Thick: 1. Calmodulin binds 4 calcium ions Ca2+-calmodulin complex

binds myosin light chain kinase (MLCK) active MLCK phosphorylates myosin light chain

ii. Thin: 1. At rest, Caldesmon positions tropomyosin to block myosin-

binding sites on actin 2. Calcium increases Ca2+-calmodulin binds caldesmon

tropomyosin moves thin filament binding sites are exposed a. Tropomyosin, but no troponin

4. How an increase in intracellular Ca2+ is sensed in smooth versus striated muscle a. Smooth muscle

i. ↑ calcium binds to calmodulin Ca2+-calmodulin complex 1. binds myosin light chain kinase (MLCK) active MLCK

phosphorylates myosin light chain 2. binds caldesmon tropomyosin moves exposes thin filament

binding sites b. Skeletal

i. Calcium binds tropomyosin exposes binding sites on actin crossbridge cycling

5. Smooth muscle contraction in the absence of ATP abundance a. Some smooth muscle can contract tonically b. “Latched state” mechanism: maintain contact between actin and myosin c. Dephosphorylation of myosin while it is in contact with actin d. Actin-myosin binding lasts longer in smooth muscle myosin phosphatase

dephosphorylates myosin while the head is still attached to actin e. Low calcium number of crossbridges in latched state is maintained sustained

force in spite of lack of ATP and its calcium influxes 6. Similarities and differences between smooth muscle and skeletal muscle contraction

a. Smooth muscle exhibits: i. latched state for tonic contraction ii. Ca2+-calmodulin regulation via myosin phosphorylation iii. Caldesmon-controlled tropomyosin positioning iv. G-protein coupled receptors (GPCRs) for opening SR calcium release

channels v. Many methods of calcium increase vi. Integration of many signals indicating degree of contraction vii. Can survive without nervous input (as in organ transplants)

b. Skeletal muscle exhibits: i. T-tubule channel conformational change for calcium release ii. Only SR calcium release iii. Signalled only by the motor neuron – and requires this input


Page 18 of 168 7. Three methods of calcium increase in smooth muscle

a. NT-linked channels (down gradient only) b. voltage-dependent channels (down gradient only) c. Ca2+ release from SR – chemically, not mechanically as in skeletal muscle:

i. GPCRs PLC IP3 calcium release 8. Four mechanisms modulating smoth muscle contractions

a. autonomic nerves b. circulating hormones c. local signals from other cells d. electrical signals from other smooth muscle cells (always excitatory)

9. Differences between multiunit and single unit smooth muscle a. Multiunit vs. single unit is determined based on the level of electrical contact

between cells b. Multiunit

i. Very few gap junctions ii. Each cell acts individually

iii. Each cell is innervated by ANS iv. Found in ciliary muscle of eye, iris, pilerector muscles

c. Single unit i. Many gap junctions electrical signals are passed rapidly wave of

depolarization cells can act as a single unit ii. poor ANS innervation

iii. Found in intestinal tract, uterus, ureters, blood vessels Principles of Cardiac Excitation and Contraction I and II

1. Normal sequence of events producing normal pattern of excitation and contraction of the heart (normal sinus rhythm)

a. Spontaneous action potentials in the sinoatrial node (SAN) i. beats are 60-100/min ii. action potentials spread rapidly through both atria and into upper AVN

b. Conduction through AV node i. slow – 0.1s ii. during delay, atria contract and assist in filling the ventricles before the

ventricles are actually stimulated c. Impulse goes from AVN through bundle of His divides into left and right

branches under endocardium, spreading down through septum, around apices, dividing into purkinje fibers covering ventricular endocardium

i. rapid conduction so that stimulation/contraction is virtually simultaneous throughout ventricles

ii. coordinated contractions pump blood into pulmonary and systemic circulations

2. Major components of the surface EKG; correspond with conduction & repolarization a. P wave: initial depolarization across right and left atria voltage deflection b. PR interval: Delay in AVN c. Q wave: depolarization of septum downward voltage deflection d. QRS complex: depolarization of ventricular myocardium e. T wave: ventricular repolarization f. QT interval: time required for complete ventricular repolarization

3. Gap junctions in mediating cardiac conduction & alteration by H+ and Ca2+ a. Muscle cells are connected in series by intercalated discs consisting of gap junctions b. Gap junctions –


Page 19 of 168 i. low-resistance electrical coupling between myocardial cells

depolarization can spread ii. can close in pathology, including myocardial ischemia produced by low pH

or high intracellular Ca2+ closure helps protect healthy cells from being damaged by ischemic neighbors

4. Ionic currents for each of the 5 phases of ventricular action a. Phase 4 – Leaking in between cycles to produce automaticity

i. K+ flows out - inwardly rectifying K current (IK1) ii. Na+ or Ca+ flows in (IH) in automatic cells

b. Phase 0 / Upstroke -- depolarization i. Na+ flows in - Na current (INa)

c. Phase 1 -- Rapid repolarization i. K+ flows in transient outward K current (Ito)

d. Phase 2 – Plateau phase i. Ca2+ flows in - L-type Ca current (ICa); Ito is inactivated

e. Phase 3 – Rapid repolarization i. K+ flows out - delayed rectifier K current (IK)

5. Which ionic currents drive conduction throughout heart chambers a. Atria INa, Ito, ICa, IK, IK1 b. Ventricles INa, Ito, ICa, IK, IK1 c. AVN ICa, IK

6. AVN role in regulating ventricular rate a. AVN acts as a filter in the current conduction by slowing transmission from atria to

ventricles and thereby regulating PR length b. Autonomic control

i. Sympathetic influence 1. NE �-adrenergic receptors GPCR cAMP Ca2+

a. ↑ ICa, heart rate (HR), contractility b. ↓ PR

ii. Parasympathetic/Vagal stimulation 1. ACh mAChR (muscarinic acetyl choline receptors) Gi

inhibits AC and opens K+ channels a. IKACh antagonizes Ca current b. ↑ PR c. ↓ HR

7. Ionic currents modulating SAN, AVN and purkinje automaticity a. Automaticity is the ability to spontaneously depolarize; cells that have this ability

start depolarizations of cardiac tissue and are called pacemakers. In these cells, the transmembrane potential is never static, because in the “at rest” state there is a net inward flux of positive ions. The diastolic (phase 4) depolarization that underlies automaticity results from an imbalance between the net inward flux of positive ions (Na+ or Ca2+) that act to depolarize the cell vs. the outward flux of K+ ions which acts to hyperpolarize the cell.

b. SAN i. T & L-type Ca2+ currents ii. Non selective IH current

1. It is nonselective for Na and K but usually conducted by Na. 2. activates upon hyperpolarization (<-70mV)

c. AVN i. similar, but rate is slower

d. Purkinje i. Too negative to open calcium channels


Page 20 of 168 ii. IH only

8. How changes in extracellular K+ alter Em, conduction velocity & automaticity a. Resting cardiac cells’ membranes are permeable to K+ Em approaches Ek b. Change [K+] Change Ek Change Em c. Normal ECF [K+] = 4mM d. Hyperkalemia ECF [K+] > 5mM

i. depolarizes Em activates less IH less depolarization decreases automaticity

ii. can change automaticity in ectopic pacemakers (pacemakers in places other than the SAN)

e. Hypokalemia i. lower Ek hyperpolarize Em: makes maximum diastolic potential

more negative activates larger IH stronger depolarization steeper phase 4 increased automaticity, potentially in ectopic pacemakers

9. Mechanisms of autonomic modulation of AVN conduction via Ih, IKACh, and ICa a. Epi b-adrenergic receptors ↑ L-type ICa in AVN ↑ Ca+2 influx during

diastole ↑ upstroke velocity ↓ AVN ERP b. Vagal stimulation ACh mAChR ↑ IKACh ↑ K+out hyperpolarization

↓ conduction velocity ↑ AVN ERP 10. Basic events linking cardiac excitation and contraction, and ionic modulation

a. Excitation-contraction coupling: i. stimulation action potential spreads across cells and into T-tubules

Open L-type Ca channels ↑ Ca trigger SR to release Ca ↑ ↑ Ca ↑ actin-myosin interaction contraction

b. Calcium entering in phase 3 of the action potential via L-type channels is insufficient to cause contraction, rather it acts as a trigger for Ca release from the SR: “Calcium-induced calcium release”

c. �-adrenergic agonists ↑ Ca release ↑ force of contraction d. Net increase in intracellular calcium during AP is regulated by Na/Ca exchange, so

Na+ gradient can influence contractility The Normal Electrocardiogram

1. Cardiac depolarization and repolarization generating flow of a current in chest a. Action potentials propagate along cardiac muscle cells b. Currents flow in complete circuits across cell membranes/through EC space c. Currents propagate through tissues and body fluids to reach skin – comparatively

small voltage is measurable at skin 2. Standard limb leads, polarity, arrangement

a. Different pairs of electrodes (leads) in strategic locations facilitate cardiac measurement:

i. I. RA-LA – negative pole at right shoulder, positive at left shoulder ii. II. RA-LL – negative pole at right shoulder, positive at left leg

iii. III. LA-LL – negative pole at left shoulder, positive at left leg b. Mnemonic: Lead # = number of Ls in name/description

3. Einthoven’s triangle a. Each lead forms one side of an equilateral, “Einthoven” triangle on the chest

4. Normal ECG and relate waves to action potentials a. P wave: initial depolarization across right and left atria voltage deflection b. PR interval: Delay in AVN

i. changes in PR duration from autonomic influence, drugs, pathology


Page 21 of 168 c. Q wave: depolarization of septum downward voltage deflection d. QRS complex: depolarization of ventricular myocardium

i. Spreads through purkinje fibers to endocardium, then to epicardium ii. Prolonged QRS from blocked Na+ channels, ischemia, or hyperkalemia

e. T wave: ventricular repolarization i. AP duration shorter in epicardium than in endocardium ii. T wave appears upright

1. During initial depolarization, endocardium is depolarized first 2. Repolarization would normally go in the opposite direction from

depolarization (i.e., down instead of up) 3. Epicardium repolarizes first, reversing the direction of the trace 4. T wave represents repolarization but appears upright as the

depolarization waves f. QT interval: time required for complete ventricular repolarization

i. Prolonged by K+-channel blocking drugs, genetic channel anomalies (long QT syndrome)

ii. Prolonged QT proarrhthymic life-threatening 5. Directionality of cardiac de/repolarization and production of EKG waves

a. Dipoles: positively and negatively charged regions of heart muscle i. formed by vectorial movements of current ii. reflect progressive depolarization/repolarization iii. Net resultant dipole direction of depolarization of heart

b. Depolarization takes place from the endocardium to the epicardium c. Repolarization takes place from the epicardium to the endocardium d. EKG recording

i. Depolarization towards the + electrode deflects the trace upward ii. Repolarization to the + electrode deflects the trace downward iii. See 4-e-ii

6. Illustration of EKG

a. Note: no waves are generated by activation of SN, AVN, His or Purkinje

7. Events in the heart relating to these intervals, significance, abnormalities i. PR interval is from beginning of P wave to beginning of Q

1. .2 seconds 2. Prolonged reflects slow conduction of impulse through AVN 3. Shortened reflects impulse being conducted over shortened route

from atria to ventricles ii. QRS is from beginning of Q spike to the end of S spike

1. includes depolarization and contraction of ventricles 2. .06-.12 seconds 3. Prolonged reflects abnormal conduction or delay of conduction

through ventricles iii. QT is from the beginning of the Q spike to the end of the T wave


Page 22 of 168 1. includes depolarization and repolarization of ventricles 2. .35-.4 seconds 3. Inverted, elevated or depressed reflect ischemia or infarction

iv. ST is from end of S spike to beginning of T wave 1. period between depolarization and repolarization 2. .12 seconds 3. Elevation or depression reflects ischemia or infarction

8. Mean QRS vector projected on Einthoven’s triangle a. Mean QRS vector or mean electrical axis of the heart is the resultant dipole of all

muscle fibers; this provides a general direction for deoplarization of the heart b. Vectorial sum of three QRS vectors from three leads c. should be between -30° and 110° (looking in clockwise direction from patient’s Left

horizontal… see page 9-10 of lecture from packet) 9. Factors causing the electrical axis of the heart to deviate from the normal range

a. >110 is right axis deviation i. R ventricular hypertrophy ii. acute right heart strain iii. left posterior fascicular block

b. <-30 is left axis deviation i. Left ventricular hypertrophy ii. Inferior wall MI iii. Left articular fascicular block

c. We do not need to memorize these Cellular Basis of Cardiac Arrhythmias

1. How myocardial ischemia causes cardiac conduction disturbance a. Ischemia

i. ↓pHin ii. ↓ATPin Opens K+ channels and loss of Na/K pump ↑[K+]out

depolarizes Em partial inactivation of Na current disturbs conduction of cardiac cells, but spares SN and AVN

2. Reentry a. Reentry aka reentrant excitation can occur during slow conduction

i. Unidirectional block: 1. Subendocardial infarcation slower conduction in damaged

pathway degradation of signal loss of signal ii. Conduction down an undamaged pathway excitation

iii. Normally, two wavefronts of depolarization meet and the ERP extinguishes them

iv. In pathology, the undamaged pathway creates a reentrant loop large stimulus in health cells jumps over damaged region

1. summation 2. elicits action potential in depressed region 3. action potential conducts upward in retrograde direction

v. retrograde impulse re-excites tissue it had previously passed through vi. Results in a repetitive circular pattern of excitation as long as the impulse

does not run into cells within the ERP 3. Conditions of reentry

a. Two parallel pathways of conduction must be present b. Unidirectional conduction block must occur along one pathway


Page 23 of 168 c. Conduction time around the circuit must be longer than the ERP of any of the cells

within the circuit – typically requires abnormally slow conduction, usually pathological or drug-induced

4. Different degrees of AVN block a. AVN block can present as

i. abnormal slowing of conduction – long PR ii. Complete failure of conduction – not every P wave is followed by a QRS

b. Degrees: i. 1st degree: Long PR, > 0.23 s; followed by QRS complex

ii. 2nd degree: Intermittent failure of AVN conduction QRS dropout 1. Mobitz type 1: Progressive PR lenghtening over successive cycles

followed by a QRS dropout AVN recovers and next beat is normal. This pattern repeats.

2. Mobitz type 2: Occasional QRS dropouts, no foreshadowing PR changes. PR can be normal or long. This type is more likely to become 3rd degree.

iii. 3rd degree: Complete AVN block. 5. Purkinje fiber automaticity and ectopic packemaking

a. Three mechanisms of ectopic pacemaker automaticity: i. Hypokalemia reduces background K+ conductance in purkinje fibers

more than in SAN ii. Ischemia Localized supersensativity to catecholamines

iii. Myocardial stretch depressed K+ conductance or leakiness (to all ions) b. Disturbances in K conductance or leakage depolarizes Em, spontaneous

depolarizations to threshold via mechanisms other than IH c. IH is the normal source of automaticity in Purkinje fibers; if pathology results in

enhanced automaticity, ectopic pacemaking may take place i. Basically this occurs if Purkinje fibers start firing faster than the SAN node;

whatever is cycling fastest sets the pace. 6. Abnormal automaticity that produce arrythmias

a. Early Afterdepolarizations (EADs) i. Secondary depolarizations occuring before repolarization is complete

(before the end of phase 3) ii. Slowed heart rate Increased number/frequency of EADs

iii. Can result from depressed K+ conductance in phases 2 & 3 iv. Etiology:

1. Tx with K+-channel blocking drugs (Class Ia or III) 2. Antiarrhytmic drugs (i.e., quinidine) 3. acidosis 4. long QT (congenital or acquired)

b. Delayed Afterdepolarizations (DADs) i. Depolarizations occur during phase 4

ii. Increased heart rate Decreased number/frequency of DADs iii. usually during calcium overload

1. Etiology a. Chronic heart disease b. Exposure to excessive levels of digoxin or catecholamies c. Hypercalcemia


Page 24 of 168

Block II: Cardiac & Renal The Cardiac Pump

1. Definitions: a. Preload: A measure of myocyte stretching in the ventricles (generally in the left

ventricle) at the end of diastole/beginning of systole. i. pratically measured as EDV

b. Afterload: The pressure in efferent cardiac vessels at the end of systole – also, can be considered as the amount of pressure against which the ventricles must pump at systolic commencement. (LV afterload = aortic pressure, RV afterload = pulmonary artery pressure).

c. Stroke volume (SV): the amount of blood pumped out of the heart with each beat. i. SV = EDV - ESV

d. Cardiac output (CO): SV * Heart Rate (HR) i. blood volume pumped out per minute

e. Ejection Fraction: The percentage of end diastolic volume (EDV) that leaves the heart at the end of systole (EF = SV / EDV)

i. normal =65% f. Stroke work (not on the list, but necessary here): SV * Ventricular Ejection

Pressure, in other words, it’s the efferent vessel pressure times the amount of fluid being pumped against that pressure. (Stroke work for LV is about 6 times that for RV).

g. Cardiac work: Stroke work * HR h. Cardiac efficiency: work output/energy expended, normally around 5-10% but can

increased by activity, and up to 25% in an athlete intensely excercising. 2. Frank-Starling and Ventricular Contraction

a. ↑Venous return ↑EDV ↑ myocyte fiber length at the end of diastole ↑SV ↑CO

b. This feature is an intrinsic phenomenon c. There is therefore a largely linear relationship between end myocardial fiber length

at the end of diastole and ventricular performance, the slope of which is increased sympathetically and decreased parasympathetically. The linear curve does plateau, and therefore cardiac output is not infinitely increased by increased EDV.

i. the plateau is a result of myocardial fibers being stretched past what they can handle

d. Propanolol blocks sympathetic innervation, decreasing HR e. Atropine blocks parasympathetic innervation, increasing HR

3. Ventricular function curve illustrates the above relationships. 4. Ventricular performance and myocardial fiber length

a. “Ventricular Performance” in 2/c can be indexed by SV, CO, Stroke work or cardiac work, all defined above. In other words, how much blood is being ejected from the heart.

b. “Myocardial Fiber Length” is indexed by the ventricular EDV, ventricular ED pressure, mean atrial pressure, and ventricular circumference. Basically, these are things that try to ascertain how distended the muscle fibers in the heart are at the end of diastole.

5. Stroke volume and Cardiac output: a. CO = SV * HR. CO is therefore affected in a parallel manner by everything

described below that affects SV, and is also increased by HR and therefore increased by sympathetic stimulation and anything that increases HR.


Page 25 of 168 i. Sedentary people increase CO primarily by increasing HR ii. Athletic people increase CO by increasing HR (even higher than a sedentary

person could) and increasing SV significantly – even up to over 50% iii. Therefore, the total amount by which a sedentary individual can increase

CO is approximately 3X, and for the well-trained athlete, CO can be increased by 6X or more.

b. SV factors: i. MOST IMPORTANT: EDV: Increased EDV increases SV up to a point

(as per Frank-Starling) 1. EDV is determined by preload

ii. HR: Increased HR decreases SV (less time for heart to fill, so increased HR decreases EDV, thereby decreasing SV)

iii. Ventricular stretchability (influences EDV), contractility (influences Ejection fraction)

iv. Afterload is also an important factor (increased afterload decreases cardiac output by reducing stroke volume)

6. Heterometric Autoregulation: two hearts beating as one a. The heart is self-regulating, and under physiological conditions, any deviation in the

balance of right ventricular output (RVO) and left ventricular output (LVO) is rectified automatically via the following relationships.

i. We want RVO = LVO so that both pulmonary and systemic circulation are full but not flooded (this doesn’t mean that the same amount of blood is in each part of the system, only that the same amount moves between systems during any one beat of the heart, keeping the total volume of each system relatively constant).

b. An increase in RVO increases the amount of blood being pumped to the lungs and therefore increases the amount of blood flowing back into the left atrium via the pulmonary vein, thereby increasing the amount of blood pumped into the left ventricle, aka EDV, thereby increasing SV or LVO. So:

i. ↑RVO ↑LA pressure ↑EDV ↑LVO c. An increase in LVO fixes itself:

i. An increase in LVO causes the next filling phase to involve an increased depletion of atrial blood, thereby decreasing the left atrial volume and pressure after the next ventricular contraction (a.k.a. the more you pump out of your ventricles, the less remains in left ventricle and left atrium).

ii. So in beat 1, too much blood was pumped out to the systemic circulation, and then in beat 2, after replenishing ventricular volume, the left atrium is depleted.

iii. This decrease in LA volume pressure also decreases the amount of volume and pressure being pumped into the ventricle in the next atrial contraction, thereby also decreasing left ventricular EDV.

iv. The decrease in EDV decreases the next LVO, so that over the few beats, the CO is self-corrected. Aren’t human bodies amazing?

v. ↑LVO ��LA volume and pressure � Left EDV �LVO 7. Methodologies of CO measurement

a. Fick principle: i. CO times (the oxygen content of oxygenated blood) = [CO times (oxygen

content of deoxygenated blood) + (the rate at which oxygen is being consumed), so:

ii. CO = Oxygen consumption rate/(Oxygen content in oxygenated blood in pulmonary veins – oxygen content in deoxygenated blood in pulmonary arteries)


Page 26 of 168 iii. Pulmonary vein flow = pulmonary artery flow = CO iv. Very little oxygen is removed from the blood between the pulmonary veins

and the capillary beds. So if you take a blood sample from a peripheral artery, not too much oxygen has been lost since that blood was in the lungs. Therefore you can use the oxygen content of peripheral arterial blood as a reasonable estimate of the oxygenation of the blood in the pulmonary veins.

v. On the same note, peripheral venous oxygenation is a fair estimate of pulmonary artery oxygenation. (A better estimate would be right atrial blood, see below for why we don’t use that…)

vi. These two values can be measured much more easily than actually catheterizing the pulmonary vessels, so peripheral oxygenation measurements are made to estimate oxygenation around the heart, allowing the calculation of CO with very minimal invasion.

8. Standard values (not an LO, but useful, I think…) a. Cardiac index means CO/Body surface area in square meters b. CO is 3146ml/m2 or about 5600 ml in a 70 kg person c. EDV is 70ml/m2 or about 125 ml in a 70 kg person d. ESV is 24ml/m2 or about 45 ml in a 70 kg person e. SV is 45ml/m2 or about 80 ml in a 70 kg person f. EF = 64%

The Cardiac Cycle

1. Chronology of events in a cardiac cycle A normal HR is 75, making a normal cardiac cycle only .8 seconds! a. Atrial systole:

i. aortic flow is 0 ii. aortic pressure is low iii. atrial pressure is higher than left ventricular pressure, causing mitral valve to

open iv. left ventricular volume is high (increases slightly during this time) v. PQR vi. Heart sound 4 is normally not heard in adults, and is the sound of

ventricular filling due to atrial systole b. mitral & tricuspid valves close

i. Heart sound 1 is caused by the mitral and triscuspid valves closing. It lasts throughout the isovolumetric contraction (below). This sound can be split, if the bicuspid closes before the tricuspid, which is a normal variation.

c. Ventricular systole i. isovolumetric contraction: this is when ventricules are starting to contract;

all four valves are closed at this point. 1. aortic flow is 0 2. aortic pressure is low 3. ventricular pressure > atrial pressure & ventricular pressure rises 4. left ventricular volume is high and static – this volume is EDV 5. S wave

ii. semilunar valves open 1. ventricular pressure surpasses aortic pressure, opening the aortic

valve iii. rapid ejection

1. aortic flow increases to its maximum


Page 27 of 168 2. the fact that the aortic valve is open allows both aortic and

ventricular pressures to reach their respective maximums, both in the neighborhood of 120 mmHg in a person with normal blood pressure (i.e., systolic blood pressure).

3. left atrial pressure drops slightly 4. left ventricular volume drops drastically 5. in the ST segment

iv. reduced ejection 1. aortic flow falls back down to 0 2. aortic and ventricular pressures decline (and by the end of this

phase, aortic pressure will exceed ventricular pressure) 3. left atrial atrial pressure is static 4. left ventricular volume continues to fall (less drastcially than during

rapid ejection) 5. T wave

d. Semilunar valves close i. this is due to the fact that the aortic pressure has now again exceeded the

ventricular pressure ii. dicrotic notch or incissura occurs: this is a decrease in aortic pressure that

dips below 0, meaning that there is backflow of blood from the aorta to the heart

iii. heart sound 2 occurs, this is the sound of the aortic valve closing e. Ventricular Diastole

i. Isovolumetric relaxation 1. all four valves are closed at this point 2. aortic flow is 0 3. aortic pressure rises from dicrotic notch and then slowly declines 4. ventricular pressure declines drastically 5. left atrial pressure increases slightly 6. left ventricular volume remains low – its value now is the end

systolic volume or ESV ii. mitral valve opens

1. this occurs at the moment that the left atrial volume and pressure exceed the left ventricular volume and pressure

iii. rapid filling 1. aortic flow is 0 2. aortic pressure is slowly declining 3. ventricular pressure declines slowly, 4. atrial pressure declines as well but exceeds ventricular pressure 5. left ventricular volume increases steadily

a. this is what causes heart sound 3, which is normally audible in children but not adults

iv. reduced filling 1. overlaps with atrial systole (reduced filling starts during atrial

diastole, and ends just before atrial systole ends) 2. the longest phase of the cycle 3. no aortic flow 4. slight decrease in aortic pressure 5. slight increases in left ventricular and atrial pressure 6. a continued rise in left ventricular volume

2. Valvular mechanisms that regulate blood flow a. atrial systole/ventricular filling – AV valves open, semilunars closed


Page 28 of 168 b. isovolumetric contraction – all four valves closed c. ventricular ejection – semilunars open, AV valves closed d. isovolumetric relaxation – all four closed

3. Pressure changes in chambers of heart and valvular action are included in chronology above

4. Ventricular pressure-volume relationship a. There is a pressure-volume loop for the left ventricle

i. pressure is y axis ii. volume is x axis

b. When mitral valve is open, pressure increases mildly until mitral closes increase in pressure aortic valve opens volume decreases aortic valve closes isometric relaxation LV pressure decreases

c. Pressure ranges from about 5 mmHg to 90 mmHg d. End systolic volume (ESV) is the lowest volume the heart ever has, or about 45 mL e. EDV is the highest volume the heart ever has, or about 150 mL f. SV = EDV – ESV; in our example, = 150-45 = 105 mL (80 is normal, so the loop

we’ve been shown is probably for an athletic elephant… page 5 of 2/7/06 packet). g. If there is an increased preload, there is an increased EDV, because of increased

venous return, and this causes an increased SV i. �preload �� venous return �EDV �SV ii. shown as increased width of the loop iii. increased preload can be due to IV infusion iv. decreased preload can be due to hemmorhage

h. If there is an increased afterload, that means there is an increased aortic pressure. The ventricle must therefore eject blood against a higher pressure, which results in a decreased stroke volume

i. ↑afterload ↑aortic pressure ↓SV ii. shown as decreased width of the loop

i. systolic dysfunction: decreased SV (aka ventricular ejection), so more blood remains in your ventricle – moves loop to the right because ESV and EDV are both increased because not enough blood is leaving the heart, so more blood must be sitting in the heart – this also narrows the loop, because SV is decreased.

j. diastolic dysfunction – your ventricles can’t relax, so the total possible amount of blood that can ever get in is reduced. So ESV stays the same but EDV decreases – so there is a narrowing of the loop. Again, SV is reduced.

5. Heart sounds are included in the chronology (#1) 6. Murmur and thrill

a. Caused by turbulent blood flow due to valvular problems, usually either stenosis (not open enough) or regurgitation (not closed enough)

b. Congenital heart defects can cause murmurs i. ventricular septal defect ii. atrial septal defect iii. patent ductus arteriosus – connects pulmonary artery and aorta iv. coarctation of aorta –aortic stenosis

1. coarctation means its being pushed together c. Systolic murmur causes

i. stenosis of semilunar valves ii. regurgitation of AV valves iii. Ventricular septal defect

d. diastolic murmur causes i. Mitral stenosis ii. Regurgitation of semilunar valves


Page 29 of 168 e. thrill, for our purposes here at least, is when a murmur is so severe that it can be felt

through the chest wall with a bare hand

Regulation of Heart Rate and Contractility

1. Cardiac autonomic innervation a. Sympathetic

i. effects: 1. vasoconstriction of vasculature (other than capillaries) 2. increased heartrate 3. increased contractility

ii. transmitters: 1. epinephrine – hormone, released from adrenal medulla, directly

enters circulation, and is degraded by monoamine oxidase (MAO) 2. norepinephrine – neurotransmitter, significantly more potent than

epinephrine (and is made into epinephrine by phenylethanomine n-methyltransferase). Because norepinephrine is not considered a hormone, it should not be measurably found in the circulation. Systemic norepinephrine implies a catecholaminergic hyperplasia.

3. in the heart, catecholamines (dopamine, epinephrine and norepinephrine are the catecholamines) decrease potassium conductance and increase calcium permeability.

4. cocaine inhibits norepinephrine reuptake (and it also blocks sodium channels, but it does a lot of more interesting things we’ll learn about later). Reuptake into the presynaptic neuron is the main way norepinephrine gets out of the synapse, though it is also metabolized by COMT and MAO in the liver.

iii. receptors: 1. alpha 1 – in vascular smooth muscle, elicits vasoconstriction 2. beta 1 – in cardiac tissue, elicits increased heart rate and

contractility (due to increased Calcium influx) a. inhibited by propanolol

3. beta 2 – in vascular (primarily pulmonary) smooth muscle, elicits vasodilation ** so asthma treatment can include sympathetic stimulation to increase vasodilation – “sympathomimetic drugs”

b. Parasympathetic i. effects:

1. vasodilation of vasculature – endothelium-dependent 2. decreased heartrate 3. decreased contractility

ii. transmitter: 1. acetylcholine, released by vagal termini 2. degraded by acetylcholinesterases – rapid breakdown into choline;

choline re-enters presynaptic terminal 3. in the heart, acetylcholine increases potassium conductance and

decreases calcium permeability iii. receptors:

1. muscarinic receptors or mAChR are found in endothelium and in cardiac tissue

a. smooth muscle: stimulation of mAChR leads to contractions


Page 30 of 168 b. cardiac tissue: stimulation of mAChR leads to decreased

contractions c. atropine inhibits mAChR

c. anatomy i. Cardiac plexus: postganglionic autonomics (both types) ii. Sympathetic: fibers are broadly and assymetrically distributed iii. Parasympathetic: vagal fibers; right vagus synapses onto SA node (therefore

affects pacemaking) and left vagus synapses onto AV node (therefore affects AV conduction)

2. Reflex pathways a. baroreceptors: ↑ pressure results ↑ stretch receptors being stretched in the

carotid sinus ↑ baroreceptor firing rate cardiorespiratory half of nucleus tractus solitarius in the medulla integrates input parasympathetic discharge

i. impairment can lead to hypertension ii. no sympathetic response from baroreceptor reflex

b. chemoreceptors: ganglia on the external carotids near the bifurcation, and on the arch of the aorta are able to sense chemical changes.

i. Mechanism: A normal concentration of ATP inhibits depolarization of ascending sensory fibers, so a decrease in ATP (aka lowered oxygen), and the presence instead of ADP, AMP and/or adenosine results in depolarization of ascending sensory fibers, which, similarly to the baroreceptor reflex, go to nucleus tractus solitarius, resulting in sympathetic discharge. There is no parasympathetic response from the chemoreceptor reflex. The following conditions result in this pathway:

1. low oxygen 2. high carbon dioxide 3. presence of cyanide 4. high plasma osmolarity

c. bainbridge reflex: Increased venous return resulting in increased right atrial volume results in stretch reception, carried by vagal fibers, ultimately resulting in an autonomically increased heart rate, which is compensatory in that it decreases the volume of blood in the right atria. Therefore, heart disease that results in right atrial distension is likely to lead to an increase in heart rate.

d. ventricular reflex: initiated by stretch receptors in the cardiac ventricles, eliciting a parasympathetic response (thereby maintaing cardiac output during increased stroke volume).

3. Reflex pathways’ factors, included throughout #2. But they all control heart rate. 4. Reflex pathways’ autonomics, also throughout #2 5. Reflex pathways’ homeostatic influences are inherent to their actions, so as long as

you know what homeostasis is, the answer is still included above. 6. Intrinsic and extrinxic myocardial factors

a. intrinsic: things that can happen without neural or hormonal influence i. heterometric autoregulation of heart (Item 6 in “The Cardiac Pump.”) ii. Frank-Starling: there is a linear relationship between EDV and CO iii. Treppe phenomenon: aka “staircase phenomenon.” Increased heartrate

leads to enhanced intracellular calcium, which in turns enhances contractile force. The result is a step-wise, continual increase in heart rate and intracellular calcium. This can be useful when suddenly increasing activity level (like sprinting, or like me trying to get out of bed in the morning).

iv. Frequency-dependent cardiac filling: cardiac filling is directly related to the length of diastole. As heartrate increases, diastolic duration decreases while


Page 31 of 168 systolic duration is static. Thus an increase in heartrate directly results in a decrease in cardiac output.

b. extrinsic: everything else we’ve learned about, so anything that includes hormonal control, autonomic innervation, etc.

i. Epinephrine: already discussed; a hormone, increases heart rate ii. Glucagon: The inotropic effects of glucagon are qualitatively similar to

those of catecholamine agents but are not mediated by the beta-receptors. As a result, glucagon can work in patients undergoing beta-blockade therapy, but catecholamines cannot gain access to the receptors. A cAMP pathway is still activated, resulting in increased heart rate contractility.

iii. Insulin: Increases calcium levels, thereby increasing contractility. iv. Thyroxin: causes an increase of beta-1 receptor expression as well as these

receptors’ affinity for catecholamine substrates. This promotes a hyperdynamic state – i.e., an increase in binding activity of sympathetic transmitters and therefore an increase in all sympathetic activities.

Hemodynamics I

1. Flow, veolicity and area

a. Velocity = Flow/cross-sectional area b. Cross-sectional area = πr2 c. Velocity represents the speed of a particle in a stream: distance/time d. Flow represents the number of particles that would pass in a unit of time:

volume/time 2. Diameter and lateral pressure

a. Total pressure is constant b. Total pressure = lateral pressure + dynamic pressure c. lateral pressure is the pressure of the fluid on the walls of the vessel d. dynamic pressure = fluid density (ρ) X v2 /2

i. dynamic pressure is in the direction of flow e. If area increases, velocity decreases, decreasing dynamic pressure and increasing

lateral pressure to maintain total pressure 3. Flow, pressure and resistance (Ohm)

a. V=IR is Ohm’s law b. E (electromotive force) = IR c. Flow (Q) = Pressure Difference (ΔP) / Resistance (R)

4. Resistance in parallel and series a. in series, resistance summates b. in parallel, resistance summates in inverse

i. 1/Rtotal = 1/R1 + 1/R2 + 1/R3… c. to calculate, if there are resistances in both series and parallel, solve for parallel first,

then count those in parallel as one in the series summation d. Total Flow (Q) = Pressure Difference (ΔP) / Total Resistance (R)

5. Factors determining flow (Poisseuille) and uniqueness of cardiovascular system a. Poisseuille’s law: F = �P�r4 / 8 L�

b. translation: Flow is equal to the difference in pressure down a tube, X �r4, over 8 X

the length of the tube X the viscosity of the fluid c. F = 1/R, resistance. Therefore resistance is directly related to the length of the tube

and the viscosity of the fluid, and is inversely related not only to flow, but also to the radius of the tube and the difference in pressure.


Page 32 of 168 d. Assumptions to make Poisseuille work, and why they don’t work in the body:

i. constant geometry of tube 1. vasculature geometry is inconsistent and dynamic

ii. rigidity and straight shape of tube 1. vasculature is curved and compliant

a. compliance is the ability to change volume in response to a change in pressure (direct relationship). Compliance encompasses distensibility and elasticity.

b. Veins are more compliant than arteries. iii. laminar flow

1. in vasculature, laminar flow exists, but turbulent flow also exists 2. laminar flow is when blood flows in parallel vectors, creating

lamellar sheets, which has a low vibration level and is highly efficient

3. turbulent flow is when blood flows in random vectors, thereby not producing lamella, which has a high vibration level and is not efficient

a. turbulent flow is what causes murmurs in the heart and bruits in the vessels

4. Reynold’s number is an index of laminar versus turbulent flow. In general, a Reynold’s number of 2000 or less reflects laminar flow, and a Reynold’s number of 3000 or more reflects turbulent flow (numbers in between we don’t have to worry about, but probably mean that both types of flow are occurring simultaneously.

a. Reynold’s # = ρDv/η b. translation: Reynold’s# = density of the fluid times

diameter of the tube times velocity over viscosity of the fluid

i. viscosity is lowest in the capillaries due to “skimming,” which is that capillaries come off of arterioles, acting as funnels, and taking more plasma than RBCs

ii. at high viscosity, “rouleaux” formation, or pancake-stacks of RBCs, are more common

iv. newtonian/ideal fluid - meaning that it is a solution, and therefore has only one component, itself. Water is Newtonian, as is saline.

1. blood is not a solution, it has blood cells, for example, so it is clearly non-newtonian, non-ideal and delicious.

2. The fact that viscosity is not constant throughout circulation is the Fahreaus-Lindquist effect (lowest viscosity is by necessity in the capillaries, as decribed above in 5-iii-b)

6. Laplace, aneurysms a. T = Pr/w b. translation: Wall tension is equal to the transmural pressure (across a wall) times the

radius of the cylinder over wall thickness c. increased pressure increases tension and diameter and decreases the thickness of a

vessel d. In a place where an artery narrows, the point just downtstream from that narrowing

is susceptible to damage because at the narrowing, velocity is increased (because diameter is reduced), therefore turbulent flow is encouraged, and the turbulent, fast-flowing blood that hits the point directly downstream is likely to increase the lateral


Page 33 of 168 pressure and wall tension (this increase is the part called the law of LaPlace), causing an aneurysm (swelling), which eventually will grow and rupture.

7. I know there’s no LO, but I think we should know… a. Mean arterial pressure and pulse pressure:

i. Pulse pressure =Systolic-Diastolic ii. Mean arterial pressure = 1/3 systolic pressure + 2/3 diastolic pressure

=1/3 pulse pressure + diastolic pressure b. blood pressure cuff sounds are audible turbulent flow produced by the cuff’s

restriction of laminar flow c. Blood pressure determinants:

i. Resistance increases Mean arterial pressure ii. Cardiac output increases Mean arterial pressure iii. Heart rate increases CO, increasing MAP iv. Stroke volume increases CO, increasing MAP v. Arterial pressure = HR*SV*R (Total peripheral resistance)

d. Capacitance relationship: relationship between transmural pressure and total contained volume of a vessel (Pressure-volume relationship)

Hemodynamics II

1. Changes in pressure, velocity, and area a. At the level of the capillaries, total cross sectional area is greatest and velocity is

lowest b. pressure drops throught system, with the greatest fall at the level of arterioles c. smallest arteries have resistance which decreases pressure before the blood enters

the capillaries. This is good because we want the lowest pressure and the lowest velocity in the capillaries – not only because we don’t want to explode the capillaries, but also because slowing down the flow of blood increases the time available for nutrient and oxygen exchange in the tissues, which is, after all, the purpose of the circulatory system.

2. Components of circulatory system (and everything about their flow) a. aorta:

i. primary conduit, thickest wall, most elastic, highest velocity, highest pressure

ii. compliance in the aorta (and arteries) minimizes pulse pressure and sustains peripheral flow:

1. during systole, the heart contracts, filling the aorta with blood 2. blood flows down aorta, but also puts pressure against aorta wall,

causing it to dilate 3. dilation of aorta creates a potential energy, the “elastic energy,”

which is stored until diastole 4. during diastole, the heart relaxes, and ceases to put pressure on the

aorta 5. the elastic energy can then be turned into its kinetic form, so the

wall of the aorta itself increases the pressure, allowing blood flow to continue

6. in this way, aortic pressure is maintained during diastole, allowing for flow to be relatively continuous

7. in disease, elastic recoil can be lost, resulting in phasic flow, so that full-on flow only occurs during systole. This can lead to a cessation of blood flow through the capillaries during diastole.

b. arteries


Page 34 of 168 i. with age, arterial compliance decreases, decreasing the average diameter

(because you can’t have need-based increases in diameter), increasing velocity (V=Q/A), and thereby increasing pulse pressure

c. arterioles i. primary sites of resistance – therefore largest pressure drop ii. large wall to lumen ratio (like a stack of donuts! not to be confused with a

stack of pancakes, which is way more like blood cells…) iii. arteriolar constriction increases arterial pressure (everything upstream of the

constriction), and decreases capillary hydrostatic pressure (everything downstream of the constriction), like what would happen if Elton John stepped on a garden hose.

d. capillaries i. aka microcirculation, capillaries are designed to be ase close to the tissue as

possible to deliver nutrients – 1. concentration of oxygen is inversely proportional to distance from

nearest capillary. 2. oxygen donation ability of the blood in the capillaries decreases

longitudinally (distally) ii. two types of capillaries:

1. continuous – like in the blood-brain barrier, proteins can’t leak out a. found in muscle, lung, CNS b. spleen editing of dying RBCs is facilitated by this type of

capillary 2. fenestrated – endothelial cells connected by diaphragms, allowing

much more in and out of the capillary a. found in sites of fluid and metabolite absorption, like renal

corpuscles (shout out to Dr.Jeter) iii. capillary permeability: pores allow water, ions and gas to get through, but

proteins can’t get out unless it’s fenestrated iv. transcapillary fluid movement: v. k(Δ�−Δπ), where k is the capillary filtration coefficient (static), P is the

hydrostatic pressure (pressure pushing out of capillaries) and π is the osmotic pressure (pressure sucking into capillaries), and differences are taken between the capillaries and interstitial fluid

1. oncotic pressure means osmotic pressure in the capillaries – created by the plasma proteins in the blood

2. There are four types of pressure, each pulling its own way (these are starling forces: fluid movement forces)

a. Pc – hydrostatic pressure of the capillary – pushes fluid from the capillary into interstital fluid

b. Pi –hydrostatic pressure of the interstitium – pushes fluid from the interstitium into the capillary

c. πc – oncotic pressure of the capillary – pulls fluid into the capillary from the interstitium

d. πi – oncotic pressure of the interstium – pulls fluid into the interstitium from the capillary (this value was 0 in the examples we were given)

e. Therefore the difference between P’s determines how much pushing there is each way and the difference between π’s determines how much pulling there is each way and the total result if you use the formula shows


Page 35 of 168 which way fluid winds up going. It winds up going out in the arterial side of the capillary bed, where the largest driving force is Pc, and back in on the venule side, where the driving force is πc.

f. Increased venous pressure (Pc) that rises above πc causes venule behavior at the capillary bed to mimic arterial behavior, resulting in enhanced filtration on the venule side, i.e., the blood flows from the venules into the capillaries and into the interstitium, which is backwards and bad for you (leads to edema and decreased venous return)

g. A significant decrease in pressure (Pc) will result in less blood being sent out to the tissues, which could result in local necrosis.

h. Starling equation: Jv = Kf[ΔP –Δπ] i. Kf is a measure of hydraulic conductance called

the “filtration coefficient” e. venules and veins

i. If arterial system is the pressure reservoir, the venous system is the actual reservoir (it holds most of the volume).

ii. high level of compliance iii. one-way valves in series facilitate unidirectional flow and reduce the height

of fluid column to be overcome at any given point (it divides the venous blood into smaller compartments making it easier for the blood to scale the body to get back up to the heart).

iv. muscle contraction facilitates venous return: 1. when muscles contract, veins are physically constricted, forcing

blood upwards 2. when muscles relax, more blood can fill the veins from below 3. blood can’t go the wrong way because of the valves

f. vena cavae i. the inferior vena cava has to take a large amount of blood to the heart

against gravity. it has the help of the thoraco-abdominal pump: 1. during inspiration, the diaphragm contracts, moving downwards.

Thoracic pressure is decreased and abdominal pressure is increased, forcing the venous blood upward, closer to the heart.

2. during expiration, the diaphragm relaxes and moves up, decreasing abdominal pressure, allowing blood flow from the lower extremities to fill the portion of the IVC that is located in the abdomen

3. if inspiration and expiration continue phasically, as in normal breathing, this mechanism will continue to help pump blood to the heart against gravity

4. in the case of a pneumothorax, increased thoracic pressure eliminates this mechanism. There will be resultant decreased venous return, decreased SV and CO.

3. Elastic recoil of aorta, blood flow and age – see 2-a-ii 4. arterioles and resistance – see 2-c 5. solute and fluid flux across capillary endothelium – see 2-d-v 6. venous circulation and gravity – see 2-e-iv and 2-f 7. lymphatic system and edema


Page 36 of 168 a. the lymphatic system helps remove fluid from the interstitium b. smallest unit is a blind sac: fluid enters blind sacs from tissue, then fluid travels

through lymphatic capillaries, collecting capillaries, and lymph vessels, to nodes, and liquid eventually returns to the systemic circulation when fluid travels through the thoracic duct into the left subclavian vein

i. smooth muscle begins at the level of the lymph vessel 1. spontaneous contraction (limited sympathetic control)

ii. lymphatic capillaries and vessels have one-way valves

Local control of Vasculature

1. Adrenergic receptors a. alpha 1

i. location: vascular smooth muscle ii. elicits: vasoconstriction

b. beta 1 i. location: cardiac tissue ii. elicits: increased heart rate and contractility

c. beta 2 i. location: pulmonary and vascular smooth muscle ii. elicits: bronchial dilation – allows greater intake of oxygen and facilitation

of fight or flight response d. dopaminergic receptors (not adrenergic, wait for the connection…)

i. elicit renal vasodilation ii. dopamine also activates beta-1 receptors iii. dopamine is converted to norepinephrine, which is converted to

epinephrine This is biochem, but looking at the physical similarities and differences between these molecules makes it feel way more logical that they all stimulate the same receptors but with different affinities.

2. Epinephrine vs norepinephrine a. Epinephrine is a hormone released by the adrenal medulla b. Norepinephrine is a neurotransmitter released by sympathetic nerve endings

i. the affinity of norepinephrine for adrenergic receptors is *much* higher than the affinity of epinephrine for these receptors

3. Local control of blood flow a. instrinsic factors

i. basal vascular tone: vessels are always partially constricted: therefore you can have change that go either way. how ingenious.

ii. myogenic response: increased transmural pressure (against the wall), pushing out against the wall, resulting in an increase in elastic recoil. this is a physical response of the smooth muscle. This is most significant in tissue where systemic pressure is likely to change because it helps equalize pressure by restricting huge increases and compensating for drops.


Page 37 of 168 iii. metabolic regulation: tissue can have enough oxygen or not. When not,

you use up your ATP and wind up with adenosine (triply dephosphorylated ATP). Adenosine is a vasodilator, which is protective because it allows greater blood flow, which helps if you don’t have enough oxygen in your blood.

1. adenosine binds to adenosine receptors (shocking) which decreases the sensitivity of contractile proteins for calcium, which relaxes arterioles (we don’t know how this happens, but we do know that the calcium concentration itself does not cause this change) increasing flow, restoring flow and oxygen

b. endothelial-derived factors: all produced by endothelial cells themselves in response to receptors or shear stress

i. NO, nitric oxide, Adrienne’s favorite chemical 1. a shear force-mediated dilator

a. Cells are in vascular wall b. shear force in this instance = luminal flow

2. increased flow through the vessels increases dilation – so during increased flow, each endothelial cell is impacted, which results in NO release, which dilates the vessels further by relaxing local smooth muscle

3. inside the endothelial cell, L-Arginine is converted to L-citruline and NO by the enzyme nitric oxide synthase

4. NO then stimulates soluble guanylate cyclase cGMP reduces calcium flux relaxing smooth muscle

5. NO is always being produced and has a short effect (half-life is about 1 second)

6. inhibition of NO can lead to hypertension 7. ACh, Bradykinin and Histamine all promote an increase in

Calcium influx, and subsequent contraction. All 3 also result in NO release, which counteracts the contraction

a. ACh stimulates release of NO synthase via endothelial mAChRs

b. Bradykinin stimulates constrction of smooth muscle and dilation of vascular tissue dilation increases NO

i. graded response c. Histamine released during anaphylactic reactions can also

promote NO release 8. more about NO and all of its amazing abilities tomorrow

ii. prostaglandins 1. actions:

a. can promote vasodilation or vasoconstriction b. those produced by platelets promote platelet aggregation

and blood clotting (thromboxane, or TXA2, is the direct clot forming factor)

c. promote renal dilation in heart failure i. COX inhibitors might promote renal constriction

and renal failure 2. synthesis:

a. arachidonic acid prostaglandins, via cyclooxygenase (COX)

b. COX 1 – gastric mucosa protection c. COX 2 –


Page 38 of 168 i. inflammation, ii. endothelium-dependent vasodilation in chronic

cardiovascular and renal disease iii. vioxx, celebrex are COX-2 inhibitors but cannot

be used in patients with the above conditions (hence the recall)

3. Non-steroid anti-inflammatory drugs (NSAIDs, i.e., aspirin) work by inhibiting both COX forms: aspirin irreversibly inhibits COX in platelets and endothelium endothelium synthesizes new COX within a few hours, but platelets cannot decreases clot formation. This is why aspirin reduces the chances of vascular clotting, stroke and MI

4. COX-2 inhibitors only inhibit COX in the endothelium, not platelet prostaglandin formation

a. COX 1 continues to make TXA2, thereby continuing to encourage clotting

b. COX 2 inhibitors are preventing anti-inflammation and reduction of clotting

c. encouraging clotting + not reducing clotting = sucks iii. endothelins

1. Peptides derived from endothelium 2. cause constriction – possible role in hypertension

Regulation of Regional Vascular Beds From page 3 of the notes, a little simplification: Structure Smooth Muscle Sympathetic Metabolic Regulation Arterioles yes yes minor Metarterioles sparse very sparse major Precapillary single fiber very sparse major sphincter Capillaries no no no Venules some yes minor Learning objectives:

1. Factors regulating coronary blood flow a. controlled almost entirely by local metabolic factors b. exhibits autoregulation c. increased metabolic activity requires more blood flow therefore an increase in

activity promotes vasodilation to facilitate increased blood access d. Work = SV * Aortic pressure e. Phasic blood flow in coronary arteries:

i. left branch: diastole lowers resistance, maximizes flow ii. right branch: less phasic & less flow

f. Cardiac perfusion factors i. metabolic regulation by adenosine: adenosine vasodilates (not enough

ATP, you must need more oxygen, better get more blood flowing…) ii. sympathetic modulation (indirect; minor role) iii. peripheral resistance (increases blood flow to heart tissue) iv. beta-1 receptor antagonists slow heartrate, increase diastole increase

perfusion and SV


Page 39 of 168 2. Severe hypotension, partial coronary artery occlusion, severe aortic stenosis – effects

on coronary blood flow, oxygen supply and oxygen demand a. stenosis: narrowing of the aortic valve increases LV pressure increases O2

consumption (without increasing work output) hypoxia, angina pectoris, cardiac failure

i. little relief from vasodilators because the vessel is already dilated, but it’s still blocked, so angioplasty would be the more effective treatment

b. coronary atherosclerosis: limits flow to heart, leading to ischemia (no collateral circulation exists here)

c. cardiovasospasm: weakness, angina, possible contributor to “sudden cardiac death” i. random constriction ii. vasodilation drug treatment helps with this (makes sense)

d. hypotension i. most commonly caused by hypovolemia ii. leads to low blood pressure iii. it may sound like it wouldn’t be as bad as hypertension, but as it turns out,

less is more. Symptoms include chest pain, shortness of breath, irregular heartbeat, fever, headache, stiff neck, back pain, productive cough, prolonged diarrhea and/or vomiting, difficulty eating, burning and foul-odored urine, allergies, seizures, and loss of consciousness.

3. Temperature, neural and local factors regulating cutaneous blood flow a. temperature

i. principal function of cutaneous sympathetic nerves ii. increased ambient temperature vasodilation, allows dissipation of heat iii. decreased ambient temperature vasoconstriction, heat retention

b. neural i. extensive sympathetic innervation mediates response to cold ii. hypothalamus responds to heat withdraws sympathetic tone lets

local parasympathetic tone take over c. local

i. cutaneous blood flow is extrinsically controlled ii. metabolic regulation iii. sweat glands

1. adjacent to parasympathetics – activation causes sweat glands to release a factor which promotes bradykinin formation vasodilation

iv. anastomosis – “shunt” 1. anastomosis constricts increases flow to distal portions of

peripheral appendages (a.k.a. fingertips) 2. highly responsive to circulating vasoconstrictors 3. no metabolic control, no autoregulation

4. Neural and local factors and myogenic mechanisms in regulating skeletal muscle blood flow

a. increase activity motor cortex releases sympathetic discharge to heart and vasculature vasoconstriction tissue becomes hypoxic local metabolic factors cause vasodilation, allowing more blood flow, and more oxygen reaches muscle

i. 20-fold dilation is required to keep up with maximum exertion b. venous pumping: rhythmic motion of skeletal muscle exerts pressure on vessels,

improving venous blood return c. neural


Page 40 of 168 i. controlled by extrinsic sympathetic innervation of blood vessels running

through skeletal muscle (arteries more than veins) ii. sympathetic innervates skeletal muscles at rest iii. adrenergic receptor stimulation:

1. alpha-1 vasoconstriction 2. beta-2 vasodilation

iv. baseline constriction peripheral resistance d. local

i. metabolic control – lactate, adenosine and potassium vasodilate 1. adenosine is most powerful

e. myogenic mechanisms i. vascular smooth muscle contracts when stretched ii. hypothesis is that increased pressure will cause constriction of vessels

5. Neural and local factors controlling cerebral blood flow (CO2, Pa) a. Cranium is incompressible & BBB limits exchanges, therefore flow in = flow out

within brain b. local regulation is the major regulatory feature

i. autoregulation is present from 60-160 mmHg (set point shifted in hypertension)

ii. high sensitivity to O2, some to CO2 c. the most important local vasodilator for cerebral circulation is carbon dioxide

increases d. vasoactive substances in systemic circulation have little or no effect on cerebral

circulation because of the blood brain barrier e. neural role is small and indirect (autonomic tone affects peripheral blood flow and

blood pressure, which affect blood being pumped to the brain, but no direct autonomic regulation exists for cerebral blood flow)

f. Cerebral ischemia i. Cushing’s phenomeon is an example of the response to cerebral ischemia ii. Increases in intracranial pressure and/or infarct, etc., anything that reduces

oxygen compress cerebral blood vessels O2 delivery decreases, medullary O2 center chemoreceptor senses sympathetic discharge to increase peripheral pressure (so that more blood can get to the brain) systemic vasoconstriction baroreceptor reflex senses high BP DECREASES heart rate

1. HR is low and BP is high (even at life-threatening levels of high) because of baroreceptor reflex – this is the defining feature

2. so you’re losing blood into your own brain. this sucks. this happens in the terminal stages of acute head injury.

iii. “Last breath” phenomenon – is the sympathetic response associated with drastically decreased oxygen – lets you gasp for breath as you’re dying

1. usually freaks the family out, but it’s great if you were drowning because you might actually live

6. No LO specifically, but we obviously have to talk about viagra. a. parasympathetic innervation is required for erection and sympathetic innervation is

requred for ejaculation (yup, you have to be relaxed to get it up, but you have to be excited to ejaculate... sounds right).

b. parasympathetic fibers lead to afferent arterioles NO cGMP vasodilation turgidity of corpus cavernosum

i. cGMP is normally degraded by a phosphodiesterase ii. Viagra is a phosphodiesterase inhibitor, so it prolongs vasodilation


Page 41 of 168 Short-term Regulation of Arterial Pressure Arterial pressure = CO * total peripheral resistance “Short term” means about 24 hours

1. Baroreceptor reflexes in arterial regulation a. baroreception is the fastest means of decreasing HR, and therefore decreasing BP b. for more information, see “Regulation of Heart Rate and Contractility” LO #2

2. Afferent and efferent neural pathways of carotid sinus/aortic arch baroreceptors a. see “Regulation of Heart Rate and Contractility” LO #2 for backstory b. in response to inspiration, pulmonary stretch receptors promote systemic dilation c. mean arterial pressure less than 100 mmHg qualifies to set off this system d. no regulation is ever “complete” – always modulatory

3. Autonomic NT and arterial pressure a. NE/Epi vasoconstriction b. ACh slows HR, decreased contractility

4. Carotid body/aortic arch chemoreception and the medulla, regulating arterial pressure

a. See “Regulation of Regional Vascular Beds” LO#5-f 5. renin-angiotensin, vasopressin, atrial natriuretic peptide in BP regulation

a. Renin-angiotensin-aldosterone system: i. low BP decrease in renal perfusion pressure renin released cleaves

angiotensinogen (from liver) angiotensin I circulates to lungs angiotensin converting enzyme (ACE) cleaves angiotensin I angiotensin II (a potent vasoconstrictor) 1. restores BP and 2. causes release of aldosterone from the adrenal cortex aldosterone increases Na reabsorption and therefore water reabsorption increased ECF volume also helps to restore BP

1. the aldosterone component of this is slow because it requires new protein synthesis, so this overall mechanism works both immediately and long term, immediately vasoconstricting and long-term increasing water retention to maintain blood volume

ii. ACE inhibition: 1. captopril (an example): blocks ACE, therefore blocks conversion

of angiotensin I to angiotensin II, limiting vasoconstriction and decreasing BP

2. losartan (another example): antagonizes angiotensin II receptors, limiting vasoconstriction and decreasing BP

a. it’s apparently ok to have excess renin and angiotensin I hanging out in your system – there are no known side effects

iii. CHF patients have high HR, low breathing rate at night, and an increased urge to urinate at night

1. Treatable with ACE inhibitors b. vasopressin (anti-diuretic hormone, or ADH)

i. vasoconstriction and water reabsorption are the actions ii. involved with longterm blood pressure regulation iii. degrades in 3-4 minutes iv. released from posterior pituitary in response to increased osmolarity (too

much concentration, so you need to keep more water) or reduced stretch in cardiac tissue (too little fluid stretching, so water is retained to restore)


Page 42 of 168 v. anything that causes fluid redistribution (changing gravity’s effects, by

escaping gravity or changing your position) will result in suppression of vasopressin (and a subsequent need to pee)

1. astronauts are given a synthetic vasopressin replacement c. atrial natriuretic peptide (ANF… F for factor)

i. released by atria in response to increased atrial pressure/stretch ii. causes vascular smooth muscle relaxation arterial dilation decreases

total peripheral resistance iii. causes increased excretion of sodium (“natriuresis”) and therefore water

reduce blood volume reduces pressure iv. inhibits renin secretion reduces pressure v. ANF is produced after a meal to promote rapid removal of sodium

1. it’s the only hormone known to cause direct sodium excretion vi. a major factor that enhances survival during heart failure

1. ANF is increased in CHF 2. Decreased contractility decreased CO increased renal

absorption (via renin-angiotensin system) increases pulmonary pressure pulmonary edema compression pulmonary resistance increases pulmonary pressure (cyclic)

3. ANF can keep a CHF patient alive for about 5 years, but it suddenly ceases to be adrenally recognized, resulting in rapid decline and death within 48 hours.

6. Time line of responses: a. Baroreceptors, Chemoreceptors, Angiotensin II within first 15 seconds b. Aldosterone is effective around 2 hours after a shift

Role of peripheral circulation in control of cardiac output

1. Measuring CO, determining effects of central venous pressure changes a. CO = HR X SV b. SV = EDV – ESV c. Central venous pressure increases EDV, increasing SV, therefore increasing CO –

up to the plateau d. SV increases with contractility and with sympathetic tone, also increasing CO

2. Changes in heart rate, myocardial contractility, preload and afterload affect CO a. preload = pressure of venous return

i. a certain amount of preload is necessary to fill the heart ii. linear relationship between venous pressure and CO in normal function

1. slope increases and decreases along with contractility a. increased contractility – sympathetic b. decreased contractility – parasympathetic (or heart failure)

2. slope has a negative correlation with changes in afterload a. decreased afterload – vasodilation b. increased afterload – vasoconstriction

3. curve shifts with increases and decreases in volume a. shift to the right (up) – increase in volume b. shift to the left (down) – decrease in volume

iii. excessive preload inability to clear vena cava blood plateau in CO b. afterload = pressure of arterial vasculature

i. work = stroke volume * afterload 3. Central venous pressure and CO (sounds strangely familiar, like question #1)


Page 43 of 168 a. At high CO, venous pressure is lowest because the heart pumps blood out of

venous circulation and into arterial circulation. As CO declines, more blood is pooling in the venous system, so reduction in CO results in an increase in venous pressure and a decrease in arterial pressure.

b. Increased VP, however, increases CO: increase volume increase venous pressure increase CO

Vascular function curves: Circle represents point of “theoretical equilibrium,” towards which the system will move under given conditions. The axes are different for the vascular curve than for the ventricular function curve in two senses. First, for the vascular curve, the Y axis is the independent variable and the X axis is the dependent variable. Secondly, for the vascular curve, the Y axis represents venous return (which is obviously correlated with CO, but isn’t exactly the same), and the X axis represents Right atrial pressure.

Heart failure: This curve shows a reduction in CO, directly resulting from decreased contractility, and causing an increase in venous pressure because more blood is pooling in the venous system. This could be a result of CHF or negative inotropic agents. Inotropic stimulation: This curve shows increased contractility resulting in increased CO, and therefore a decrease in venous pressure (because more blood is ejected from the heart, removing it from venous circulation). This could be a result of positive inotropic agents (eg. digitalis), or sympathetic tone.


Page 44 of 168 Blood loss or venous dilation: This shows a shift in the vascular curve but not the ventricular curve – so now the CO is decreasing and venous pressure is decreasing, both because of decreases in blood volume (hemorrhage) and/or increases in compliance.

Volumetric expansion: Here the vascular curve has shifted to the right, increasing CO and venous pressure. Underlying causes: water retention, transfusion, i.e., increases in blood volume, or decreases in venous compliance.

Arterial constriction: An increase in Arterial constriction reduces the amount of blood reaching the venous side, thereby reducing venous pressure. Arterial constriction separately increases the afterload, thereby decreasing SV, thereby decreasing CO, thereby increasing ESV, thereby increasing venous pressure for the blood trying to get into the heart. So CO is definitely decreasing, but VP is both increasing and decreasing, so VP tends to break even.

Arterial dilation: Arterial dilation increases the flow through the arteries to the venous system, increasing VP. At the same time, arterial dilation decreases afterload, increasing SV and CO, decreasing ESV, decreasing VP. So this time, CO is increased, but VP again is increasing and decreasing and there is ideally no net effect on VP.


Page 45 of 168 The effects of progressive increases in volume: initial increase improves CO, but further increases are futile as the plateau has been reached. Therefore extra volume will not improve CO but will result in edema. This can happen when a person with compromised cardiac function is given a transfusion, because the set point is decreased, and the heart is unable to adapt to the new increased volume, resulting in respiratory distress. Instead of transfusing a patient, administering drugs that increase contractility (dobutamine, dopamine, ionotropics, digitalis) might buy the patient time.

Circulatory Shock

1. Hemorrhage and hypovolemic shock a. insufficient oxygen/nutrient delivery diffuse irreversible deterioration

complete system failure b. shock types are categorized based on the nature of the initiation c. Hemorrhagic shock is the most common form of hypovolemic shock

i. blood pressure can be maintained despite blood loss, but CO will decrease ii. patients can survive acute hypotension, only to die a few days later from

multiorgan failure (renal, etc) due to ischemia 2. Compensation for hypovolemia

a. Compensated shock is non-progressive – generally an early stage of shock i. always some compromise of nutrient delivery ii. can have reduced BP iii. can have reduced CO

b. In compensated phase, negative feedback mechanisms are protective against low arterial pressure

c. Mechanisms: i. sympathetic activation

1. baro and chemoreceptors (seconds) 2. arterial pressure falls parasymp withdrawn increased HR

CO & BP increased (or attempted) 3. increase HR, contractility, total peripheral resistance,

vasoconstriction, decreased compliance a. vasoconstriction occurs in peripheral tissues but not in

coronary or cerebral vascular beds b. sympathetic innervation increases arterial pressure, but

what is really desired is increased arterial supply or flow – so although sympathetic activation can prolong life somewhat, it isn’t really targeting the problem appropriately – all tissues other than the prioritized heart and brain wind up starving for nutrients

4. Full-blast sympathetic activation stimulates vasoconstriction but also reduces ventricular function (because it decreases diastole and therefore decreases EDV, decreasing SV), so you’re increasing


Page 46 of 168 arterial pressure and decreasing cardiac output at the same time – so not that much blood is going to get to the tissues expediently

ii. CNS ischemia (minutes) 1. decreased oxygen oxygen deficit accumulation of CO2 in

blood/fall in pH sympathetic discharge via chemoreceptors attempts to restore cardiac output and blood pressure

2. in the brain, medulla is extremely sensitive to O2 changes, reinforcing sympathetic tone

iii. renin-angiotensin-aldosterone (minutes to hours) 1. a fall in arterial pressure fall in renal perfusion pressure

renin-angiotensin system – angiotensin II promotes vasoconstriction attempt to restore blood pressure (impairs CO)

iv. vasopressin increase (minutes) v. reabsorption of extravascular fluid (hours) vi. renal remodeling (days)

3. Decompensatory mechanisms – acidosis, end-organ failure (heart, kidney, intestine, liver)

a. Decompensated phase is 25% normal CO or less b. progression involves systemic deterioration secondary to reduced perfusion

i. “irreversible” = inevitably fatal c. Progressive phase:

i. deteriorating blood pressure ii. deteriorating CO iii. Rouleaux / thrombosis / sludging

1. sludging: decreased blood velocity increased blood viscosity cells stick together

a. limited oxygen b. macrophages are blocked c. venous resistance increased

iv. capillary damage v. increased venous resistance vi. increased oxygen deficit vii. lactic acidosis / loss of catecholaminergic response

1. build-up of CO2 & increase of anaerobic response lactic acid buildup lowers pH denatures catecholaminergic receptors

a. dopamine can bind past when NE & Epi can, so dopaminergic drug therapy is a good last-ditch effort

viii. endotoxins 4. Hemorrhagic shock treatment

a. DON’T give a transfusion in cardiac as per the last LO set, it’s only going to cause edema, so the patient will drown in the blood you perfuse

b. dobutamine/dopamine/glycosides are the only thing that might help (see 3/c/vii/a) – anything that will increase contractility

c. see below in chart Fleshed out “Pocket Guide” to shock: Here these forms are separated into clean little categories we can memorize, but in real life shock is often a combination of these things. Type: Hypovolemic Examples: blood or plasma loss – like as in burn victims Primary Problems: decreased circulating volume decrease in CO


Page 47 of 168 Initial hemodynamic changes: There is a decrease in total volume, therefore obviously a decrease in central venous pressure, because less blood is pooling in the venous system. This is what causes the decreased CO. Sympathetic innervation also increases TPR in an attempt to compensate. Treatment options: transfusions, plasma expanders Prognosis: reasonable if treated early Type: Cardiac Examples: extensive infarct Primary Problems: decreased contractility decreased CO Initial hemodynamic changes: There is decreased contractility, so therefore there is decreased CO. Meanwhile, blood is waiting to get into the heart in the venous system, and it backs up, increasing central venous pressure. Sympathetic innervation increases TPR in an attempt to make flow constant. Treatment options: no infusions! drugs which increase cardiac contractility Prognosis: very poor Type: Vasodilatory Examples: anaphylaxis, endotoxins Primary Problems: extensive peripheral vasodilation Initial hemodynamic changes: Vasodilation means decreased peripheral resistance, so the CO is increased because it is pumping against a much-decreased afterload. Since CO is increased, more blood is being pulled out of venous reservoirs, so there is decreased central venous pressure. Treatment options: glucocorticoids, antihistamines, vasoconstrictors Prognosis: reasonable if treated early Type: Neurogenic Examples: anesthesia overdose, brain damage Primary Problems: decreased CO, extensive peripheral vasodilation Initial hemodynamic changes: Neurogenic shock is a result of sympathetic collapse. So all sympathetic activities should cease, resulting in decreased peripheral resistance, but also decreased CO, so even though afterload is reduced, the heart still is pumping out at a lower rate, so like in cardiac shock, blood is waiting in the venous system to be pumped, and there is an increase in central venous pressure. Treatment options: pacemaker, vasoconstrictors Prognosis: poor Renal hemodynamics and regulation of glomerular filtration rate

1. Renal fraction of CO: define, calculate, factors a. 20% of CO is in the renal fraction = 1.2 L or 4 ml/min/gram

i. this is one of the highest rates in the body, and it delivers more oxygen than the kidney can use

b. Renal fraction = Renal blood flow (RBF) / CO i. RBF = total renal flow / combined weight of kidneys

c. Factors: i. arterial pressure ii. blood composition iii. neural imputs iv. hormonal signalling

2. Average values for RBF, GFR and compare blood flow and O2 consumption in renal tissue and skeletal muscle

a. RBF: 1200ml/min b. GFR: 130ml/min c. Blood flow is much higher in renal tissue than in skeletal tissue, and more oxygen is

consumed in renal tissue than in skeletal tissue, but proportionately (amount of


Page 48 of 168 oxygen consumed over amount of blood perfused), skeletal muscle consumes more oxygen than the kidneys

3. Filtration fraction: define, calculate a. Filtration fraction = GFR / RPF b. Translation: Glomerular filtration rate / Renal plasma flow = the amount of the

plasma coming through the kidneys are able to filter c. usually about .17-9

4. Extrinsic/intrinsic factors regulating RBF and renal vascular resistance, and predicting changes in RBF and GFR from changes in sympathetic tone and increased epinephrine

a. Intrinsic i. autoregulation:

1. maintenance of glomerular pressure and filtration rate despite systemic changes – because of smooth muscle surrounding afferent vessels, which adjusts for changes in incoming pressure

a. decreased systemic pressure afferents dilate b. increased systemic pressure afferents constrict

ii. macula densa-tubular glomerular feedback (TGF) 1. increases in flow through macula densa vasoconstriction 2. decrease in flow through macula densa vasodilation 3. this is a smooth muscle response, like in section 4/a/i/1 4. TGF mechanism is responsible for long-term control of Na+/H20

balance, and thus extracellular fluid volume maintenance 5. increase in arterial pressure increased in afferent renal pressure

an increase in GFR increased flow to distal tubule increased chloride delivery to macula densa change in osmolality causes macula densa to release hormones signals for constriction of afferent arteriole GFR is brought back down

iii. myogenic mechanism 1. increase in wall tension (passive response to elevated arterial

pressure) vascular smooth muscle contraction – this is exhibited by afferent arterioles and interlobular arteries

b. Extrinsic i. circulating vasoactive agents or renal sympathetic nerve activity ii. Sympathetic innervation, Hypotension or decreased sodium delivery

kidney releases renin cleaves hepatic angiotensinogen to angiotensin I pulmonary ACE cleaves to angiotensin II systemic vasoconstriction & causes adrenal cortex to release aldosterone increased electrolyte reabsorption increased water reabsorption, sensation of thirst

iii. Sympathetic tone 1. stress, trauma, hemorrhage, pain and exercise all cause sympathetic

discharge, which increases renal vascular resistance 5. Renal vascular resistance sites, hydrostatic pressure profile

a. resistance mainly occurs in afferent and efferent arterioles, drastically reducing the mean pressure, so: mean pressure is stable in arteries reduced in afferents stable in glomerular capillaries reduced in efferents stable in peritubular capillaries reduced slightly in veins

b. RA = PRA – PG / RBF c. RE = PG – PC / RBF - GFR d. In glomerular capillaries, fluid comes out of vessels into nephronic tubular space,

because of the higher hydrostatic pressure in the capillary than in bowman’s space,


Page 49 of 168 so there needs to be reduced glomerular pressure just so that the poor teeny capillaries won’t explode, but pressure still must exceed that of bowman’s capsule so that liquid will go into nephronic tubular space

e. In peritubular capillaries, liquid is being reabsorbed into systemic circulation, having been filtered, so now the pressure needs to be even lower than in the glomerular capillaries, because it needs to be lower than the pressure in the bowman’s capsule so that liquid will come back into the capillaries (the math is below)

f. PG=60, PB=20, PI=6 (I is the interstitium). This all works out well because we need the pressure in the bowman’s capsule to push out less than that of the glomerular capillaries, so that liquid will go from the capillaries into the bowman’s capsule

g. πC=37, PC=20, so the total sucking power in the peritubular capillaries is 17. If Pc were 60 (i.e., if there were no additional resistance in the efferent arterioles, so that Pc=PG), then no liquid would enter the peritubular capillaries, because have you would 37 mmHg pushing into the capillaries (πc) but 60 pushing out (PC), and no liquid would ever re-enter circulation. So Pc is reduced to a level where the total difference in pressures would pull into the capillaries to facilitate net reabsorption, and sure enough, a Pc=20 will allow plenty of liquid back in.

6. Hydrostatic/colloid osmotic pressure in regulating glomerular filtration rate, filtration barriers in the glomerular membrane, protein and macromolecular restriction

a. Pressure question – See #5 b. Filtration barriers in glomerular membrane

i. three layers 1. inner: fenestrated endothelium – walls are 90-95% complete,

fenestrations have no diaphragams, this allows small molecules through

2. outer: basement membrane – made of mucopolysaccharides and proteoglycans. It is negatively charged and has pores with a radius of 50 Å.

3. sticking out from the basement membrane: podocytes, which have negatively charged slit pores.

4. Something about the combination of the basement membrane’s pores and the podocyte’s pores stops macromolecules (albumin, antibodies) from going through

c. Protein/macromolecular restriction 7. Calculating net filtration for glomerular filtration, Kf

a. GFR = Kf(PG-PB-πG) = Kf * EFP (Effective filtration pressure) b. Kf is the filtration coefficient, decreased by:

i. hypertension ii. diabetes iii. glomerulosclerosis decrease

c. An increase in RA decreases RPF and GFR, but GFR goes down more i. PG is also reduced ii. aka, if resistance increases on the plasma’s way in, it will decrease pressure

and flow, so there will be less perfusion and also less filtration going on d. An increase in RE decreases RPF and GFR, but RPF goes down more

i. PG is increased ii. aka, if resistance increases on the plasma’s way out, it will decrease flow but

it will increase pressure, because more liquid is trying to get through than can – so there will still be drops in both flow and filtration, but there will be less of a drop in filtration because the pressure is keeping the liquid


Page 50 of 168 pumping into filtration more than in the case of increased afferent resistance

8. Renal autoregulation, tubuloglomerular feedback, myogenic mechanism – see #4/a/i/2

9. RBF/GFR changes from angiotensin II, increased prostaglandin E2, increased NO, increased renal sympathetic tone

a. angiotensin II – an increase in angiotensin II will stimulate aldosterone release, which increases total water reabsorption, and will discourage filtration. RBF and GFR are reduced – less liquid is coming through the kidneys and less liquid is leaving the body, to conserve water. But GFR is reduced less than RBF, so the filtration fraction is even higher

i. proximal tubular reabsorption is increased ii. thirst stimulated iii. enhances sympathetic activity iv. arterioles (A & E) constricted

1. efferents are affected way more v. increases sensitivity of TGF mechanism vi. decreases Kf by reducing hydraulic conductivity of glomerular capillaries vii. inhibits renin release negative feedback viii. (See #4/b/ii for more info on angiotensin II)

b. prostaglandin E2 i. produced from arachidonic acid via cyclooxygenase (COX) ii. promotes renal vasodilation increases RBF and GFR iii. protective effect against vasoconstrictor stimuli, hypovolemia, hypotension iv. Non-steroidal anti-inflammatory drugs (N-SAID’s) are COX inhibitors

reduce prostaglandins reduces opposition to vasoconstriction decrease RBF, GFR and Na excretion

c. NO i. cGMP vasodilation increases RBF and GFR ii. preglomerular and postglomerular arterioles are both responsive to NO

blockade GFR decreases less than RBF d. renal sympathetic tone – see # 4/b/iii

i. tonic sympathetic innervation on renal hemodynamics is minimal ii. low level -- increases renin release, increases tubular Na reabsorption iii. moderate levels – increase afferent and efferent arteriolar resistance,

reduces both GFR and RBF – but RBF is reduced more than GFR iv. high level

10. Changes in tubular reabsoprtion association with pressure changes in peritubular capillaries – see #5

Clearance principle and assessment of renal function

1. Derive clearance equation, be able to determine clerances for creatinine, inulin, p-

amino hippuric acid a. Clearance is an evaluation of nephronic handling of a given substance

i. clearance is the minimum amount of liquid that must pass through into the bowman’s space in order to account for the amount of that substance in the urine

b. For a substance S i. Clearance = amount of S excreted in urine / plasma concentration of S ii. amount of S excreted in urine = urine flow X urine concentration of S


Page 51 of 168 c. If S is something that is completely passed (i.e. p-amino hippuric acid or PAH),

clearance = renal plasma flow d. If S is something that is completely reabsorbed (such as glucose), clearance = 0. e. If S is neither completely passed nor reabsorbed, some of the time we can use the

equation below – In using this equation we are making a basic assumption that the percentage of S that passes (from the plasma into the Bowman’s capsule) will be approximately equivalent to the percentage of plasma that comes through into the Bowman’s capsule. This is perfectly true for S= creatinine, inulin, and some other compounds, but the formula can also be used as an estimate for the passage of many other substances that have a similar filtration pattern (i.e., fit the criteria in 1/e/ii).

i. Equation: GFR = UF*SU/SP 1. Translation: Glomerular filtration rate = Urine flow *

Concentration in the Urine / Concentration in the plasma ii. Criteria to use this equation (these are characteristics of creatinine and

inulin): 1. excreted via filtration 2. filtered without restriction 3. no net reabsorption or secretion 4. not metabolized anywhere in the tubules 5. amount excreted = amount filtered

iii. Derivation: 1. Amount filtered = GFR X SBS 2. Amount excreted = UF X SU 3. GFR X SBS = UF X SU 4. SBS = SP 5. GFR X SP = UF X SU 6. GFR = UF*SU/SP 7. QED ;)

2. Explain which clearances represent glomerular filtration rate (GFR), and renal plasma flow (RPF) and explain criteria

a. GFR is represented by creatinine and inulin i. because they fit all of the criteria in 1/e/ii, which basically means that the

amount being filtered and the amount being excreted in urine are the same b. RPF is represented by PAH

i. This is because all of the PAH that comes through the kidney comes out of the body. So the total amount of plasma flowing through the kidney can be estimated by the amount of PAH that comes out of the body.

3. Given plasma and urine concentrations and urine flow, calculate filtered load, tubular transport, excretion rate and clearance for a substance S

a. Filtered load, FL = GFR*SP b. Tubular transport = FL – excretion rate

i. we think this is the same thing as “net reabsorption,” or the amount reabsorbed across the tubules

c. Excretion rate = Urine concentration * Urine formation rate d. Clearance = tell your mom to see 1/b e. Explain how changes in filtration, reabsorption and secretion will affect excretion

i. Increased filtration increase excretion ii. Increased reabsorption decrease excretion iii. Increased secretion (i.e., from efferent capillaries back into tubules)

increase excretion 4. Determine net tubular reabsorption vs. secretion by comparing clearance to GFR


Page 52 of 168 a. if clearance < GFR – that means you have net reabsorption (for a given S) b. if clearance > GFR – that means you have net secretion (for a given S) c. transport maximum aka tubular maximum: the maximal rate of secretion or

reabsorption of a substance by the renal tubules. Glucose, for example, has a tubular maximum for reabsorption – 375mg/min. Glucose will be excreted into the urine (glucosurea) if blood glucose is above 300mg/dl.

Proximal tubule Transport mechanisms

1. Basic principles of epithelial transport, characteristics of active transport, facilitated diffusion, passive diffusion with regard to energy source and carrier protein involvement

a. Reabsorption is achieved via both active and passive transport b. active transport uses energy and goes against the concentration gradient

i. primary needs ATP directly 1. in tubular cells, occurs at basolateral membrane

ii. secondary uses concentration gradient produced by primary 1. in tubular cells, occurs at apical membrane 2. in this particular case, efflux (from tubular cell to peritubular fluid)

of sodium in primary transport is actually facilitating influx of sodium (from tubular lumen into tubular cell) in secondary transport by reducing the concentration inside the cell and therefore changing the concentration difference between the inside of the cell and the lumen of the tubule

iii. active is subject to limitations: 1. metabolic inhibition – ATP is required, therefore a depletion in

ATP will lead to decreased ability to pump against a gradient 2. competitive inhibition – amino acids, for example, can compete for

the same protein carrier 3. transport maximum (Tmax) – the rate of reabsorption for any

substance whose transport is active may have a limit. For example, reabsorption of glucose is by secondary active transport via a sodium glucose cotransporter. The number of sodium-glucose carriers is limited, so at plasma glucose concentrations > 350 mg%, carriers are saturated – making this amount the Tmax.

c. facilitated diffusion works down a concentration gradient but requires a carrier protein


Page 53 of 168 d. passive diffusion does not require either energy nor a carrier protein

2. Contribution of proximal tubule and other major nephron segments to the reabsorption of the filtered load of water and solute

a. proximal tubule is responsible for most of the reabsorption – hence it is reffered to as the “bulk reabsorber.” It is the location of the reabsorption of:

i. 67% NaCl reabsorbed ii. 100% glucose iii. 80-85% HCO3 iv. lots of phosphate, sulfate, lactate, citrate, succinate (the organic anions)

b. descending limb of henle: i. no active NaCl transport

1. but there is passive transport ii. high permeability to water iii. some permeability to urea and NaCl

c. thin ascending limb of henle: i. completely impermeable to water ii. some permeability to urea and NaCl

d. thick ascending limb of henle i. completely impermeable to water ii. Has active transport of NaCl out of the tubule creates the driving force

for Na/K/2Cl cotransporters (which bring 1 Na, 1 K and 2 Cl into the tubular cell from the lumen of the tubule)

1. this provides K inside the cell, which will leave down its own gradient, creating an electrochemical difference (negative inside the cell), creating a positive charge outside the cell, which will push luminal sodium away (positive charge repelling) and into the blood (it travels between the cells of the tubule in order to get from lumen to blood). This is called “paracellular diffusion,” being that it is diffusion occuring next to a cell.

3. Major transport functions of proximal tubule with regard to sodium, chloride, potassium, bicarbonate, hydrogen phosphate, glucose, amino acids and urea

a. Sodium – See #2 b. Chloride – See #2

i. Chloride is not absorbed early on in the proximal tubule, which means that as fluid is reabsorbed (as you go distally) chloride concentration increases, therefore in the distal portion of the proximal tubule, chloride diffuses into the tubular cells, down its concentration gradient. The negative charge that the chloride brings with it creates a potential difference between the lumen and the tubular cells, which is used in passive distal reabsorption of cations

c. Potassium i. Passively reabsorbed in late proximal tubule

d. Bicarbonate i. ATPase pumps Na out and K in ii. Na/H antiporter pumps Na in and H out iii. H in the tubular lumen combines with HCO3 H2CO3 (carbonic acid) iv. H2CO3 CO2 + H20 via carbonic anhydrase v. water passively diffuses across tubular cells and back into peritubular fluid vi. the carbon dioxide diffuses into tubular cells, where it is hydroxylated back

into HCO3 by cytosolic carbonic anhydrase (again) vii. Now bicarbonate can be cotransported with sodium out of the tubular cells

into the peritubular space e. Hydrogen phosphate


Page 54 of 168 i. 85% of filtered phosphate is reabsorbed in the proximal tubule by a sodium

phosphate cotransporter f. glucose

i. 100% of reabsorption is in the proximal tubule by a sodium cotransporter g. amino acids

i. 100% of reabsorption is in the proximal tubule by a sodium cotransporter h. Urea

i. 100% of reabsorption is in the proximal tubule ii. 50% of filtered urea is reabsorbed passively in the proximal tubule

4. Generation of tubular osmotic forces a. As sodium is reabsorbed from the tubular lumen, across the tubular cells and into

the renal interstitium, the concentration in the renal interstitium becomes higher than that in the tubular lumen, which pulls water out of the lumen and into the peritubular space

b. luminal hypotonicity: In the proximal tubule, osmolality is 275-280mOsm/kg. The proximal tubule is very permeable to water, therefore water will flow out to meet higher ion concentration. Originally, it was thought that the lumen was isotonic, and though this has turned out not to be quite true, this flow is still referred to erroneously as “isoosmotic reabsorption”

c. Axial Anion Assymetry: As you travel distally down the proximal tubule, the concentration of biocarbonate decreases and the concentration of chloride increases. In the late proximal tubule, the reflection coefficient (σ) is high for bicarbonate and low for chloride. The reflection coefficient is the degree to which something cannot traverse a membrane, so the high σ of HCO3 means that it cannot diffuse back into the lumen freely, and the low σ of Cl means that it can diffuse back into the lumen freely. Therefore there will effectively be a significant concentration gradient for HCO3 but not for Cl.

i. HCO3 gradient that occurs accounts for 90% of total water reabsorption

5. Flow-dependent regulation of proximal tubular reabsorption underlying glomerulotubular balance

a. Glomerulotubular balance is based on starling forces in peritubular capillaries, which alter the reabsorption of sodium and water in the proximal tubule. The route of isoosmotic fluid reabsorption is from the lumen, through the tubular cells, to the renal interstitum and into the peritubular capillaries.

b. Starling forces in the peritubular capillary blood govern the amount of reabsorption of isoosmotic fluid

c. Starling forces for those of you just joining us (like us) are the summation of sucking in and pushing out pressures across a membrane (P’s and π’s)

d. See “Renal hemodynamics and regulation of glomerular filtration rate” part 5 g e. The more fluid we send into the tubule, the more concentrated the efferent blood

will be, and therefore the more fluid will have to re-enter the peritubular capillaries from the tubules in order to achieve physiological osmolality in the blood

Loop of Henle and countercurrent system

1. Describe and contrast the mechanisms of solute and water transport by the

descending segment of the loop of Henle a. NaCl is passively transported but not actively b. high permeability to water c. some permeability to urea and NaCl


Page 55 of 168 2. Explain how transport and permeability characteristics of the descending and

ascending segments of the loop of Henle enable the kidney to produce a concentrated urine

a. See Proximal tubule transport mechanisms #2/c & d b. Descending limb

i. water out of lumen increases concentration ii. urea into lumen iii. NaCl – only slight permeability

c. Ascending thin limb i. Sodium and chloride ions diffuse out into interstitium

d. Thick ascending limb i. pumping chloride into interstitium ii. passive follow of sodium into interstitium iii. no water permeability no diffusion out iv. solute concentration in interstitium has increased

e. distal convoluted tubule i. now permeable to water again, water goes out to meet ions ii. urea is left inside distal convoluted tubule with fewer ions and less water

urine has a concentration of urea that is much higher than the blood concentration of urea, but urine does not have as much water or as many ions as does the blood

3. How renal tubular handling of urea contributes to concentrated urine production a. See #2

4. Process responsible for dilute urine production, and effects of changes in vasopressin (aka anti-diuretic hormone or ADH) levels

a. Water deprivation increased plasma osmolarity stimulates osmoreceptors in anterior hypothalamus ADH secretion from posterior pituitary increased water permeability of distal tubule and collecting duct increased water reabsorption increased urine osmolarity & decreased urine volume & decreasing plasma osmolarity

b. Water abundance decreased plasma osmolarity inhibits osmoreceptors in anterior hypothalamus suppression of ADH decreased water permeability of distal tubule and collecting duct decrease water reabsorption decreased urine osmolarity, increased urine volume, increased plasma osmolarity

i. High-ceiling diuretics such as furosemide (Lasix) bind to the Na/K/2Cl transporter and inhibit ionic influx. If you can’t pump ions out of the loop of Henle, water won’t follow them, and urine output will increase and have a lower concentration of urea, as well as a higher concentration of water and electrolytes

5. No LO, but “Counter currents” seemed pretty important to address, considering their place in the title of the lecture:

a. Countercurrent just means that there is a semipermeable membrane with fluid on either side and that there is exchange of properties (in this case, concentrations) between the two fluids

b. Loop of henle acts as a countercurrent mulitplier: this is the phrase for the long-described above phenomenon that concentrates urine

i. Countercurrent mulitplication depends on NaCl reabsorption in the thick ascending limb and countercurrent flow in both descending and ascending limbs of Henle


Page 56 of 168 c. Vasa recta – countercurrent exchanger (these are the blood vessels right by the loop

of Henle, so they’re obviously absorbing some of the fluid and ions coming into the cells of the walls from the lumen)

d. Countercurrent arrangement – I think this is just how everything is sitting together in it’s little limbed, hair-pinned way that lets countercurrent stuff occur.

Distal tubule and collecting duct

1. Mechanisms of solute and water transport by distal tubule and collecting duct segments

a. 25% of filtered NaCl is reabsorbed in the loop of Henle b. 8-9% of filtered NaCl is reabsorbed in the distal tubule and collecting duct

i. this amount is smaller, but this is the part that’s most regulated, so it’s actually the part that determines how much reabsorption will take place

c. Early distal tubule i. Distal convoluted tubule cells ii. impermeable to water iii. NaCl reabsorption via cotransporter but no reabsorption of water

dilution of tubular fluid iv. “cortical diluting segment”

d. Late distal tubule (aka connecting tubule) i. Two cell types:

1. connecting tubule cells – a. reabsorb NaCl and water b. secrete potassium c. Aldosterone increases sodium reabsorption and potassium

secretion d. ADH increases water permeability (reabsorb more water)

2. intercalated cells – a. secrete H+ by a H+-ATPase, which is stimulated by

aldosterone b. reabsorbed K+ by a H+/K+-ATPase (from BRS; not

stressed in lecture) e. Collecting duct

i. distal tubules of several nephrons confluence into 1 collecting duct ii. water reabsorption occurs in presence of ADH iii. two types of cells:

1. NaCl is transported by principal cells 2. intercalated cells

iv. Collecting duct goes through cortical and medullary renal layers just as the loop of henle does

v. cortical collecting tubule 1. water leaves 2. main function is to raise both fractional and absolute luminal

concentration of urea vi. outer medullary collecting tubule

1. water leaves 2. raises absolute concentration of urea

vii. inner medullary collecting tubule 1. water leaves 2. urea concentration is now high so some urea also leaves


Page 57 of 168 a. this helps maintain the high concentration of urea in the

inner medulla urea recycling: when urea is reabsorbed from the collecting duct, it enters the inner medullary portion of the loop of Henle. This is necessary in order to maintain the high urea concentration of the inner renal medulla, because if the urea there were not being replenished, it would soon be depleted by the inner medullary portion of the loop of Henle, into which urea diffuses. A high concentration in the inner medulla is important because it makes water diffuse out of the lumen, concentrating the urine in the loop of Henle.

b. ADH increases permeability of the inner medullary collecting tubule to urea, allowing more urea to be reabsorbed into inner medullary interestitium

3. maximum concentration is achieved here 2. Factors modulating distal tubule and collecting duct transport function

a. Thiazide diuretics (like hydrochlorothiazide) inhibit the transporter that symports sodium and chloride from the lumen into the cells of the early distal tubule

b. amiloride inhibits sodium reabsorption and therefore NaCl reabsorption in the apical membrane of principal cells of late distal tubules

i. therefore also inhibits K+ secretion – therefore “potassium-sparing” 1. other potassium-sparings are spironolactone & triamterene

c. If furosemide is given upstream of the DCT it’s a potassium-wasting diuretic i. it inhibits NaCl reabsorption in the thick ascending limb of henle

absorbing Na+ makes you secrete K+ ii. If you’re on furosemide, you take a separate K+ supplement

d. Sodium reabsorption in late distal tubule and collecting duct: i. tubular flow causes sodium to go from the lumen into the cells

potassium goes from cells into lumen 1. an increase in sodium flow increases sodium, chlorine and water

reabsorption and potassium secretion ii. an increase in plasma potassium concentration increases sodium

reabsorption iii. aldosterone – a mineralocorticoid secreted by adrenal cortex mRNA

aldosterone-induced proteins a. Na+/K+ pumps b. increase in krebs enzymes feed ATP into Na+/K+

pump 2. increases sodium reabsorption and potassium secretion

a. induces apical Na channels b. induces basolateral Na+/K+ pumps c. therefore sodium gets pulled from lumen into cell and

then out into interstitium 3. Tubular segments and cellular mechanism by which ADH increases permeability to

water and urea a. ADH increases water permeability by directing the insertion of water channels into

the luminal membrane. In the absence of ADH, principal cells in the Late distal tubule and collecting duct are virtually impermeable to water

b. V1 receptors are on vascular smooth muscle cells and arterioles i. ADH binding causes vasoconstriction, decreases in RBF and GFR ii. Mechanism is IP3/Ca-mediated


Page 58 of 168 c. V2 receptors are on the basolateral membranes of Late distal tubule and collecting

duct i. cAMP PKA phosphorylation results in the insertion of aquaporins

in the apical membranes (aquaporin II, specifically) 4. Two major mechanisms controlling ADH release and negative feedback

a. ADH originates primarily in the supraoptic nuclei of the hypothalamus b. Factors that increase ADH secretion:

i. an increase in serum osmolarity (main mechanism) 1. Water deprivation increases serum osmolarity stimulates

osmoreceptors in anterior hypothalamus increases ADH secretion from posterior pituitary increases water permeability of late distal tubule and collecting duct increases water reabsorption increases urine osmolarity and decreases urine volume, decreases plasma osmolarity toward normal

ii. volume contraction = decrease in blood volume 1. decreases inhibition of osmoreceptors, increasing their activity,

increases the excitability of the osmolarity mechanism iii. pain iv. nausea v. hypoglycemia vi. nicotine, opiates, antineoplastic drugs

c. Factors that decrease ADH secretion: i. a decrease in serum osmolarity

1. Water intake decreases plasma osmolarity inhibits osmoreceptors in anterior hypothalamus decreases ADH secretion decreases DCT/CD permeability to water decreases water reabsorption decreases urine osmolarity and increases urine volume and increases plasma osmolarity toward normal

ii. ethanol iii. alpha-agonists iv. ANP

d. It takes a 15% change in blood volume to result in a change in vasopressin release (in either direction), but only a 2% change in plasma osmolarity. Despite the fact that the system is more sensitive to plasma osmolarity, ultimately a change in blood volume above the 15% threshold will override changes in plasma osmolarity if the two have opposing effects. In other words, your body won’t care that you’re not sweating if you just hemorrhaged.

Renal Hormones

1. Identify the Renal Hormone Systems Regulating Renal Function a. The major renal hormone system is the Renin-Angiotensin-Aldosterone System,

which is essential for Na+ and H2O balance i. Decreases in blood volume cause a decrease in renal perfusion pressure,

which in turn increases renin secretion. ii. The enzyme renin is produced by the Juxtaglomerular (JG) cells of the

afferent arteriole iii. Renin catalyzes the conversion of systemically circulating angiotensinogen

to angiotensin I, which is then converted to angiotensin II (ANG II) by angiotensin converting enzyme (ACE) which is present in the highest


Page 59 of 168 quantities in the pulmonary endothelial cells, and then in the kidneys, but it present on endothelial cells throughout the body. In the kidneys ACE is located in the interstitium and the basolateral membrane of the proximal tubule (PT) cells

iv. ANG II is the biologically active octapeptide which then acts on various membrane receptors, resulting in vasoconstriction, and increasing the total peripheral resistance and elevating the blood pressure back to normal

v. ANG II also elicits Aldosterone release from the zona glomerulosa of the adrenal cortex.

vi. Aldosterone release causes increased renal Na+ reabsorption, thereby restoring extracellular fluid (ECF) volume and blood volume to normal

vii. The actions of Aldosterone include: 1. ↑ Renal Na+ reabsorption (action on the principal cells of the late

distal tubule and collecting duct) 2. ↑ Renal K+ secretion (action on the principal cells of the late distal

tubule and collecting duct) 3. ↑ Renal H+ secretion (action on the intercalated cells of the late

distal tubule and collecting duct) b. Renal prostaglandins (PGs), also play a critical role in regulating renal function

i. Cyclooxygenase (COX) converts arachidonic acid into different classes of prostaglandins (or autocoids, since they act at site of production)

ii. COX 1 and COX 2, both eventually convert arachidonic acid to PGI2 and PGE2 (as well as Thromboxane 2, TXA2)

iii. PGE2 and PGI2 are potent vasodilators. Both ↑ RPF and ↓H2O reabsorption by the collecting duct

1. PGE2 acts on glomeruli, thick ascending limb, and collecting duct 2. PGI2 acts on thick ascending limb, and collecting duct 3. PGE2 and PGI2 inhibit the action of ADH on LDT and CD,

thereby ↓ water reabsorption by the LDT/CD

4. Under normal volume conditions, there is no substantial PG effect. However, When ECFV is compromised and vasoconstricting mechanisms are activated, then PGs play a crucial role in Na+ and H2O balance

iv. ECFV depletion resulting from ↓ Na+ intake, ↓ Blood Pressure, or intense dehydration causes ↑ PGE2 and PGI2 production

1. PGs counteract the vasoconstriction of ADH and ANG II 2. COX-Inhibitors (e.g. Vioxx), prevent the formation of PGs,

leading to increased unopposed vasoconstriction, which can result in renal failure with chronic use or in a patient whose ECF is already depleted extensively

c. Bradykinin, is another potent hormone that promotes vasodilation i. Bradykinin is produced from a cascade of transformations, taking Renal

Prekallikrein to Bradykinin; all of which occurs in the LDT

ii. Bradykinin opposes the actions of ANGII, and ↑ NaCl excretion and ↑ H2O excretion

iii. Bradykinin also stimulates PG production (PGE2 and PGI2)

iv. Renal PGs and Bradykinin are potent renal vasodilators, leading to ↓ Na+

reabsorption and ↓ H2O reabsorption, which antagonizes the vasoconstriction by ADH and ANG II


Page 60 of 168 d. Erythropoietin (EP) is important in the generation of RBCs and ultimate

sustenance for the kidneys themselves i. 90% of EP is synthesized in the kidneys

ii. EP stimulates Hematopoietic stem cells to become proerythroblasts (that will ultimately become RBCs)

iii. ↓ O2 delivery to the kidney, results in ↑ EP synthesis, leading to ↑ RBC synthesis, ↑ Hematocrit, ↑ability to deliver O2 to kidneys

iv. Chronic ↓ O2 delivery to the kidney resulting from ↓ blood volume or chronic anemia, leads to chronic renal vasoconstriction, and eventual renal failure

1. can also result from constriction of the afferent renal arteriole v. Renal failure/Dialysis patients cannot produce their own EP, so they

receive injections 2. The major stimuli that influence regulation of these renal hormone systems:

The most important regulatory factors are ECF balance and blood volume. These renal hormone systems have the ability to preserve normal ECFV homeostasis and adequate arterial pressure. There are 3 mechanisms that act to regulate cAMP levels and intracellular [Ca2+] of the JG cells of the afferent arterioles in response to changes in ECF balance and blood volume.

a. Baroreceptor mechanism: JG cells of the afferent arteriole act as baroreceptors and respond to changes in transmural pressure gradient between the afferent arteriole and interstitium

i. Afferent arteriole acts as a stretch receptor: Increased stretch leads to decreased renin secretion

ii. Increased renal arterial pressure, increased stretch of afferent arteriole, which increases JG cells’ membrane stretch, which causes stretch-activated Ca2+ channels in the JG membrane to allow Ca2+ to rush down its concentration gradient into the JG cell cytoplasm.

iii. Increased intracellular [Ca2+], decreases renin secretion – since renin promotes constriction, a decrease in renin allows dilation, lowering blood pressure and bringing flow back down towards normal

iv. Conversely, if renal arterial pressure is decreased, there is decreased stretch on the afferent arteriole and decreased JG membrane stretch, leading to decreased intracellular [Ca2+] and increased in renin secretion

b. Sympathetic Innervation i. Proximal tubule (PT) and distal tubule (DT) cells are innervated by

sympathetic efferent fibers. ii. JG cells are also innervated by sympathetic efferents that release

Norepinephrine (NE), that acts on β1-adrenergic receptors of the JG cells, leading to increased intracellular [cAMP] and a consequent increase in renin secretion

1. For example, a decrease in renal arterial pressure activates increased sympathetic tone increased NE release increased cAMP increased renin secretion vasoconstriction return in pressure towards normal

c. Macula Densa (MD) mechanism involves increasing or decreasing Renin secretion (distinct from the Tubuloglomerular feedback mechanism in which MD cells communicate with the afferent arteriole to elicit vasoconstriction)

i. Macula densa cells are located between the thick ascending loop of Henle and the distal convoluted tubule

ii. Macula densa cells function as chemoreceptors and are stimulated by decreased NaCl load


Page 61 of 168 iii. Any stimulus that increases flow through the thick ascending limb of the

loop of Henle, leads to the increased delivery of tubular fluid Na+ to the macula densa cells of the JG apparatus

iv. Increased Na+ delivery (from increased GFR, resulting from increased blood pressure), results in decreased renin secretion to release vasoconstriction of systemic vessels causing decreased blood pressure, decreasing GFR

1. ECFV expansion a. Increases blood volume increasing blood pressure

increasing renal blood flow increasing GFR increasing the Na+ delivery to the MD cells.

i. Na+ reabsorption requires ATP, thus more Na+ reabsorption (from increased GFR) leads to a depletion of ATP, increasing the concentration of Adenosine.

ii. Adenosine acts on JG cells increasing intracellular [Ca2+] and decreasing Renin secretion

2. ECFV depletion a. Decreases BV, decreasing BP, decreasing RBF, decreasing

GFR. Decreases Na+ delivery to MD cells, leading to an increase in renin secretion

3 & 4 Summary of major effects on renal function and interaction of hormone systems d. Renin-Angiotensin System

i. Potent vasoconstrictor: increases cardiac contractility, increases ADH release, increases sympathetic tone, increases vasoconstriction, increases NE release, increases Aldosterone release

ii. ANG II has direct vascular and transport effects 1. ANG II constricts both afferent and efferent renal arterioles,

leading to decreased RPF and an increased Filtration Fraction (FF), leading to increased proximal tubule fluid reabsorption

2. Constricts the renal mesangial cells, leading to a decrease in the filtration coefficient (Kf), which if severe enough can decrease GFR (GFR = Kf ⋅ EFP)

3. Direct stimulation of proximal tubule reabsorption of NaCl, HCO3- and H2O

e. Aldosterone, release stimulated by ANG II, causes increased NaCl and H2O reabsorption to increase BV and hence increase BP

f. Prostaglandins, promote vasodilation to offset the vasoconstriction of ADH and ANGII

g. Bradykinin also promotes vasodilation to antagonize ADH and ANGII vasoconstriction

h. Erythropoietin enables increased O2 delivery, elicited by decreased renal perfusion and O2 delivery

The Kidney in Blood Pressure Regulation and Pathophysiology of Hypertension 1. Major neurohumoral and cardiovascular mechanisms responsible for long-term

regulation of arterial blood pressure: To maintain blood volume (and hence blood pressure) within a normal range, the kidneys regulate the amount of water and sodium lost via the urine. There are several mechanisms, which maintain sodium balance, extracellular fluid volume, and blood volume. This is important because hypertension can lead to strokes, MI, renal dysfunction, vision loss, and endocrine disease.


Page 62 of 168 a. Neurohumoral Systems (this is basically all review)

i. Arterial Reflexes 1. Myogenic autoregulation; vasoconstriction in response to increased

pressure, vasodilation in response to decreased pressure 2. Tubuloglomerular feedback mechanism; increased blood pressure

increased RBF increased NaCl delivery to macula densa vasoconstriction of afferent arteriole to decrease RBF

ii. Atrial Reflexes 1. Increased atrial stretch due to increased blood volume, leads to

vasodilation iii. Renin-Angiotensin-Aldosterone System

1. Vasoconstriction and increased Na+ and H2O reabsorption iv. Adrenal Catecholamines

1. Vasoconstriction v. Vasopressin (Anti-diuretic Hormone, ADH)

1. Increased Na+ and H2O reabsorption vi. Atrial Natriuretic Peptide/Factor (ANP/ANF)

1. increased blood volume increased blood pressure atrial stretch Vasodilation

2. Increased Na+ excretion by inhibiting Na+ reabsorption in collecting tubule cells

vii. Endothelial Factors (Nitric Oxide, Endothelins) 1. Vasodilation in response to increased pressure and flow

viii. Kallikrein-Kinin System 1. Leads to Bradykinin production; vasodilation

ix. Prostaglandins & Other Eicosanoids 1. Vasodilation to offset the vasoconstriction of ADH/ANG II

b. Cardiovascular mechanisms i. The two major determinants of arterial pressure: 1) cardiac output and 2)

peripheral resistance ii. On a long-term basis

1. mean circulatory pressure and blood volume depend on sodium balance which is regulated by the kidneys

2. arterial pressure is linked to the ability of the kidneys to excrete sufficient salt to maintain normal sodium balance, extracellular fluid volume and blood volume

2. Normal range of dietary sodium intake and the relationships between sodium balance, plasma volume and CV hemodynamics: Salt concentration is regulated, so an increase in salt results in an increase in water reabsorption.

a. Normal Range of Dietary Sodium Intake i. Many people consume 1,150- 5,750 mg/day -- that is termed the "hygienic

safety range" of sodium intake1 b. Plasma Volume changes with increases in salt intake

i. Increased salt intake increased plasma volume increasing blood pressure ii. The maintenance of blood pressure depends on the ability to get rid of the extra

salt by a variety of neurohumoral mechanisms a. Decreases in sodium excretory capability chronic

increases in ECFV and BV which result in hypertension c. The integration of sodium exchange sodium ECF level

1 “Salt and Health” http://www.saltinstitute.org/28.html


Page 63 of 168 i. Quantity of NaCl in ECF / Extracellular Fluid Volume =

Na+ and Cl- concentrations in ECF ii. Increased NaCl intake Increased NaCl in ECFV ADH release

Concentrated urine (increased free water reabsorption) and thirst (increased water intake)

iii. Decreased NaCl intake Decreased NaCl in ECFV ADH inhibition Dilute urine (increased solute-free water excretion)

d. Osmolality is rapidly regulated by adjusting the ECF volume to the total solute present i. [NaCl] in ECF is regulated by an indirect measurement of volume:

1. Increased NaCl intake increase ECFV stretch receptors in CV Therefore volume and not concentration is the effective measured variable.

3. NaCl regulation along the nephron a. Proximal Tubule: reabsorbs 2/3 of filtered Na and H2O

i. Early proximal tubule, basolateral Na+-K+ ATPase, decreases cellular [Na+] for Na+ reabsorption

1. Na+ is reabsorbed by cotransport with glucose, amino acids, phosphate, and lactate

2. Na is also reabsorbed by countertransport via Na+ - H+ exchange, which is linked directly to the reabsorption of filtered HCO3-

ii. Middle and late proximal tubules 1. Na+ is reabsorbed with Cl-

iii. Stimulation of Na+ reabsorption 1. ANG II via Aldosterone 2. Adrenergic agents of increased renal nerve activity 3. Increased luminal flow or solute delivery

iv. Inhibition of Na+ reabsorption 1. Volume expansion 2. Atrial Natriuretic peptide 3. Dopamine 4. Prostaglandins

b. Thick Ascending limb of the loop of Henle: reabsorbs 25% of filtered Na+ i. Contains a Na+-K+-2Cl- cotransporter in the luminal membrane ii. Is the site of action of the loop diuretics (eg. furosemide), which inhibit the

Na+-K+-2Cl- cotransporter iii. Is impermeable to water NaCl is reabsorbed without water tubular fluid

[Na+] and tubular fluid osmolarity decrease to less than their plasma concentrations. This segment is called the diluting segment

iv. Na+-K+ ATPase increases intracellular [K+] lumen-positive potential difference, which raises driving force of K+ secretion driving force for the Na+-K+-2Cl- cotransporter and paracellular diffusion of cations from the tubule lumen to the pericapillary fluid

v. Stimulation of Na+ reabsorption 1. ADH 2. β-Adrenergic agents 3. Mineralocorticoids (aldosterone)

vi. Inhibition of Na+ reabsorption 1. Hypertonicity 2. Prostaglandin E2 3. Acidosis

c. Distal Tubule and Collecting Duct: together reabsorb 8% of filtered Na+


Page 64 of 168 i. Early distal tubule

1. Reabsorbs NaCl by a Na+-Cl- cotransporter 2. Is the site of action of thiazide diuretics which block the Na+-Cl-

cotransporter – on apical membrane 3. Is impermeable to water reabsorption of NaCl occurs without water,

which further dilutes the tubular fluid 4. Is called the cortical diluting segment

ii. Late distal tubule and collecting duct: have 2 cell types 1. Principal Cells

a. Reabsorb Na+ and H2O b. Secrete K+ c. Aldosterone increases Na+ reabsorption and K+ secretion.

i. Like other steroid hormones, the action of aldosterone takes hours to develop because new protein synthesis is required

d. ADH increases H2O permeability by directing the insertion of H2O channels in the luminal membrane. In the absence of ADH, the principal cells are virtually impermeable to water

e. K+-sparing diuretics (spironolactone, triamterene, amiloride) decrease K+-secretion

i. Is the site of action of amiloride diuretics which block the apical Na+ channel blocking sodium influx results in decreased Cl influx and K efflux

1. because K efflux (i.e., secretion) is decreased, amiloride is “potassium-sparing”

2. α-Intercalated cells a. Secrete H+ by a H+-ATPase, which is stimulated by

Aldosterone b. Reabsorb K+ by a H+,K+-ATPase (not emphasized in class)

3. Stimulation of Reabsorption a. Aldosterone b. ADH

4. Inhibition of Reabsorption a. Prostaglandins b. Nitric Oxide c. Atrial Natriuretic Peptide d. Bradykinin

4. The Renin-Angiotensin-Aldosterone System – Key in regulating blood pressure and sodium excretion

a. Decrease in blood volume decrease in renal perfusion pressure increase renin secretion: Renin, catalyzes [angiotensinogen angiotensin I], angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE)

b. ANG II i. Constricts resistance vessels (predominately via AT1 receptors in the adult)

thereby increasing systemic vascular resistance and arterial pressure ii. Activates adrenal cortical release of aldosterone

1. Aldosterone causes kidney to increase sodium and fluid retention 2. Aldosterone activates mineralocorticoid receptors in collecting duct

cells to increase production of Na+/K+ ATPase on the basolateral membrane, and also sodium and potassium channels on the luminal membrane (increased production of these proteins ultimately results in more sodium retention)


Page 65 of 168 iii. Stimulates the release of vasopressin (ADH) from the posterior pituitary which

acts upon the kidneys to increase fluid retention iv. Stimulates thirst centers within the brain v. Facilitates norepinephrine release and inhibits norepinephrine reuptake vi. Stimulates cardiac and vascular hypertrophy

c. Angiotensin II Receptor Subtypes and Renal Actions i. Subtype 1A and 1B

1. Increase arterial pressure 2. Increase aldosterone release increase Na+ reabsorption 3. Afferent and efferent vasoconstriction 4. Mesangial cell (support cells in the glomerulus) contraction

decreases Kf (i.e., makes cells less permeable, allowing less liquid to get into the glomerulus, decreasing water loss)

5. Increased sensitivity of TGF mechanism a. Increased sensitivity of afferent arteriole to signals from

macula densa cells 6. Increase Na+ reabsorption

a. In the proximal tubule: Stimulate Na+/H+ exchanger activity (apical, amiloride sensitive) and Na+/HCO3- co-transporter (basolateral)

b. In the distal tubule: Stimulate Na+/H+ exchanger activity 7. Decrease Renin secretion (negative feedback) 8. Increase Endothelin, TXA2, Reactive Oxygen Species

ii. AT2 type receptor (fetal/embryonic) 1. Vasodilator effect 2. Inhibit cell proliferation 3. Stimulate Bradykinin 4. Stimulate nitric oxide synthase

5. Major tubular transport mechanisms and commonly used diuretics that block transport mechanisms

a. Thick Ascending Limb of the Loop of Henle i. Furosemide (a diuretic indicated for edema) blocks the luminal Na+-K+-2Cl-

cotransporter 1. Increases NaCl excretion 2. Increases K+ excretion 3. Increases Ca2+ excretion 4. Decreases ability to concentrate urine, (because of decreased

corticopapillary gradient) 5. Decreases ability to dilute urine (because of inhibition of diluting

segment) b. Distal Tubule

i. Thiazide blocks the luminal Na+/Cl- co-transporter in the early distal tubule. Amiloride blocks the luminal Na+/H+ exchanger in the early distal tubule.

1. Increase NaCl excretion 2. Decrease K+ excretion 3. Decrease Ca2+ excretion 4. Decrease ability to dilute urine (because of inhibition of cortical diluting

segment – aka early distal tubule) 5. No effect on ability to concentrate urine

c. Collecting Duct Cells i. Amiloride blocks the luminal Na+ channel (in the principal cells) and Na+/H+

exchanger (in intercalated cells)


Page 66 of 168 1. Increase Na+ excretion 2. Decrease K+ excretion (used in combination with loop or thiazide

diuretics) 3. Decrease H+ excretion

6. Pressure Natriuresis Increased blood volume increases arterial pressure, renal perfusion, and glomerular filtration rate. This leads to an increase in renal excretion of H2O and Na+ that is termed pressure natriuresis. Pressure natriuresis is modulated and regulated by other systems…

a. Low Blood volume Renin-Angiotensin-Aldosterone system increased sodium retention increased water retention

i. Both angiotensin and aldosterone, although by different mechanisms, stimulate distal tubular sodium reabsorption and decrease renal sodium and water loss

b. Low Blood Volume vasopressin (ADH) release water reabsorption in the collecting duct decreasing water loss & increasing blood volume

7. Hypertension from renal impairments Hypertension results from an underlying defect in the ability of the kidneys to adequately handle sodium. Increased sodium retention could then account for the increase in blood volume.

a. Chronic increase in “effective” blood volume (i.e. increased cardiac output) i. Hypervolemia

1. Renal artery stenosis 2. Hyperaldosteronism 3. Hypersecretion of ADH 4. Aortic Coarctation 5. Pregnancy (preeclampsia)

b. Inappropriate activation of one of the many vasoconstrictor systems (i.e. increased systemic vascular resistance)

i. Stress (sympathetic activation) ii. Atherosclerosis iii. Renal artery disease (increase ANG II) iv. Pheochromocytoma (increased catecholamines) v. Thyroid Dysfunction vi. Diabetes vii. Cerebral Ischemia (Cushing’s phenomenon)

c. ANG II-Dependent Hypertension can cause: i. Increased arterial pressure and pulse pressure ii. Increased aldosterone secretion iii. Activation of Endothelins, Thromboxane, and reactive oxygen species iv. Activation of cytokines and growth factors

d. When hypertension is sustained, possible results: i. Vascular injury ii. Stroke iii. Coronary Arterial disease iv. Kidney damage and fibrosis in many other tissues

Mechanisms of Acid Base Balance I & II: HCO3 Reabsorption & H+ Secretion; Tritatable Acids & NH4 Excretion Whole body acid-base balance and the role of the kidney

1. The normal rates of daily acid production and the sites of elimination. a. We produce acid at a rate of 1mEq/kg/day, so for an average 70 kg person, 70

mEq/day is produced on a typical diet. b. The acid must all excreted by the kidneys.


Page 67 of 168 2. The importance of bicarb/CO2 buffer system and the use of the Henderson-

Hasselbach equation in interpreting acid-base homeostasis. a. The bicarb/CO2 buffer system is the highest capacity buffering system in the body. b. CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3 c. This equation can be written as the Henderson-Hasselbach equation:

i. pH=6.1 + log (HCO3/.03 x p CO2) ii. We can calculate any of the three variables provided by this equation (pH,

bicarb, or CO2) from any two other variables. (i.e. if we have two, we can get the third… isn’t that the point of algebra?)

3. Four “Simple” types of acid-base disorders (metabolic/respiratory acidosis/alkalosis) and the direction of changes in HCO3, CO2, and pH in each disorder with measurement of arterial “blood gases.” Understand the concept of the “anion gap” in diagnosis of metabolic acidosis.

a. Acid Loads i. Respiratory acidosis- an increase in CO2 levels (possibly from respiratory

depression, emphysema, anything that makes you not breathe out as well) 1. Alveolar ventilation should increase to maintain constant CO2

levels. Alveolar ventilation is controlled by chemoreceptors in the medulla which are sensitive to pH.

a. Decrease in cerebral pH increases ventilation lowers pCO2 levels

2. The chemoreceptors respond more rapidly to increased CO2 levels than increased non-volatile acid levels

3. Simply by mass action, an increase in CO2 will lead to an increase in H+ and HCO3

a. In chronic respiratory acidosis, renal compensation occurs: HCO3 reabsorption is increased, which helps bring pH higher, towards normal.

ii. Metabolic acidosis- caused by an increase in non-volatile acids. These can include phosphoric and sulfuric acid which are dietary byproducts. Non-volatile acid is what makes up the 70 mEq/day that our kidneys excrete. When the non-volatile acid load exceeds what the kidney can excrete, metabolic acidosis ensues.

1. In an arterial blood gas test HCO3 plasma levels are lowered. The loss of the alkali component is equivalent to the addition of acid, so CO2 and pH levels decrease. (See Henderson-Hasselbach for clarification)

b. Alkali Loads i. Respiratory alkalosis- excess CO2 removal (resulting from

hyperventilation) 1. CO2 loss H+ and HCO3- loss pH increases

a. Renal compensation: i. decreased excretion of H+

ii. decreased reabsorption of new bicarb ii. Metabolic alkalosis- caused by an increase in non-volatile alkali

(exogenous from the diet or a decrease in acid excretion) 1. Not usually caused by an increase in alkali from a normal diet 2. Reflected in arterial blood gas by increased HCO3 plasma levels,

constant CO2 levels, and increased pH. c. Anion gap- depleted plasma anions (Cl or HCO3)

i. Normally when you add up all the ions in the blood (Na, K, Cl, and bicarb) the charge will be about +12. If the Cl or bicarb is depleted, the charge


Page 68 of 168 difference between anions and cations will be even greater (so the charge will be greater than 12). This indicates the presence of metabolic acidosis.

ii. This is the measure most frequently used to determine if acidosis is the result of increased H+ ions or decreased bicarb.

4. Compensation for acid-base disorders a. Two cases and a brief explanation from the old notes b. A primary change in one system (respiratory (lungs) or metabolic (kidneys)) results

in a secondary change in the other system to compensate for the pH change. c. Case #1- respiratory alkalosis

i. Moving to an area with increased altitude causes a great demand for O2, so you breathe faster.

ii. When you breathe faster (hyperventilate) there is a drop in pCO2 leading to respiratory alkalosis

iii. Over the next few days your kidneys will excrete more HCO3 into the urine to lower the pH back to a normal value.

iv. Thus, the primary change in the respiratory system causes a secondary metabolic change.

d. Case #2- metabolic acidosis i. A patient with uncontrolled type I diabetes develops ketoacidosis (a form of

metabolic acidosis) ii. As his pH falls, the respiratory rate will increase to lower pCO2 levels,

which will raise the pH to normal in a matter of minutes. iii. Thus, a primary change in metabolism causes a secondary change in the

respiratory system to compensate. 5. Two major tasks of the kidney in acid-base balance: bicarb reabsorption and

generation of “new” bicarb (by urinary acid excretion) a. The kidneys play a major role in regulating systemic bicarb levels by regulating two

processes. Urine is generally free of bicarb, so almost all that is filtered (4.5 moles per day) will need to be reabsorbed along the course of the nephron (mostly in the proximal tubules).

b. In addition, the kidney is responsible for generating additional bicarb. The kidneys produce bicarb by the excretion of acid in the urine (secretion of acid is equal to production of alkali). Bicarb is produced at the same rate that acid is secreted: 1 mEq/kg body weight/day, replacing the amount of bicarb occupied in acid buffering.

6. Components of net acid excretion (NAE). a. Acid cannot be secreted in the urine as protons (urine pH is about 4.5, but that does

not account for all the acid we must secrete). b. There are two main processes by which acid is excreted by the kidneys: excretion of

titratable acid and the excretion of ammonia. About half the acid is excreted by each method.

i. Titratable acid refers to excretion of a proton coupled to a urinary buffer. The chief urinary buffer is phosphate.

ii. Ammonia (NH4+) helps in the formation of bicarb. Thus if it is excreted it represents the formation of new bicarb (or acid secretion). More details in next section.

c. NAE= titratable acid + ammonium – urinary bicarbonate i. The loss of other organic ions is not quantitatively important in calculating

whole body acid-base balance

Specific Renal Mechanisms of Acid-base transport 1. General characteristics of proximal and distal tubules in acid-base transport


Page 69 of 168 a. Proximal tubule reabsorbs about 75-80% of total filtered bicarb.

i. Most bicarb reabsorption is driven by the Na/H exchanger located on the apical surface of the tubule cells: H+ is secreted combines with bicarb

forms carbonic acid broken down into CO2 and water. 1. Some H+ is also secreted via an H-ATPase

ii. CO2 diffuses across cell membrane combines with OH- (via the help of carbonic anhydrase) Bicarb pumped back into the blood (via a Na-3 HCO3 exchanger on the basolateral surface).

b. Distal tubule – intercalated cells are responsible for acid/base exchange i. The intercalated cells secrete H+ via an H+/ATPase pump located on the

apical membrane. Also, the distal tubule wall is fairly impermeable to ions. ii. A transepithelial pH gradient is generated (this is not possible in the

proximal tubule since it is permeable to ions) urine pH < 5 because of the combined acid secretion and ion impermeability.

iii. The proton secretion will result in bicarb reabsorption if bicarb is present in the distal tubule (probably only if there is some pathology of bicarb absorption in the proximal tubule).

2. Apical and basolateral membrane transport characteristics of the proximal tubule. Know the role of carbonic anhydrase.

a. See above, question 1.a. i. and ii. 3. Factors that regulate proximal tubule bicarb reabsorption.

a. Factors that increase bicarb reabsorption: i. Decreased cellular pH ii. Increased systemic pCO2 iii. Decreased peritubular bicarb levels iv. Chronic potassium depletion v. Chronic acidosis (increases apical Na/H exchangers and basolateral

Na/bicarb transporters) vi. Decreased ECF volume (in general in low volume states you reabsorb more

solute so that you can reabsorb more water from the tubules) vii. Angiotensin II viii. Hypercalcemia

b. Factors that inhibit bicarb reabsorption i. Parathyroid hormone ii. Increased peritubular bicarb iii. Increased cellular pH

4. General features of the collecting duct that mediate acid-base transport. a. Collecting duct, like the distal tubule, is capable of generating a large transepithelial

pH gradient (urine <5, blood ~7.4) b. H+ secretion (accompanied by Na reabsorption) is stimulated by mineralocorticoids c. Otherwise, the collecting duct functions much like the distal tubule.

5. General features of ammonium production and excretion by the kidneys. a. Ammonia is excreted in the proximal tubule. b. The predominant precursor of ammonia is glutamine (each glutamine forms one

bicarb and one ammonia molecule). Most of the ammonia ends up in the urine. c. Glutamine NH4+ + [alpha-ketogluterate CO2 HCO3 ] d. If NH4+ is reabsorbed, the HCO3 from glutamine will combine with it to form urea

which will be excreted, so generation of HCO3 causes no change in acid-base balance

e. If NH4+ is not reabsorbed, it will be excreted in the urine and represent the true formation of a bicarb ion.


Page 70 of 168 i. Thus NH4+ in the urine represents acid excretion (see 6.c.i. for NAE

equation) Integrative function of the kidneys

1. How sodium balance determines ECF and response to ECF depletion a. As we learned in block 1, changes in ionic concentration lead to changes in fluid

retention and compartmentalization in order to maintain ideal osmolarity. Sodium balance is what ultimately determines ECFV and therefore controls all pathological states of volume change.

b. Sodium depletion i. caused by: vomiting, diarrhea, severe burns, intestinal obstruction, diuretics

c. Sodium excess i. caused by:

1. CHF extracellular volume depletion Na reabsorptive mechanisms increased ECV edema, JVD, etc.

2. nephrotic syndrome, cirrhosis, renal failure 2. General distribution of potassium in ECF and ICF and the role of the kidneys in

potassium regulation a. Potassium Standards:

i. ECF 3.5-4.5 mEq/liter ii. ICF 140-150 mEq/liter iii. Total body stores: 3500 mEq iv. Daily intake 100mEq

b. Renal potassium i. Excretion of potassium is predominantly via the kidneys

1. determined by secretion in distal convoluted tubule ii. reabsorbed mostly in the proximal tubule

3. Mechanisms regulating potassium uptake from ECF into cells a. maintained by Na/K pump b. Factors driving potassium into the cells:

i. Insulin (by stimulating basolateral Na/K ATPase pump) ii. beta-adrenergic agonists iii. mineralocorticoids iv. glucocorticoids v. alkalemia vi. high HCO3 vii. hyposmolarity (K flows into cell along with water) viii. Alkalosis – exchange of intracellular H+ for extracellular K+

4. Mechanisms regulating potassium excretion in the urine a. Factors increasing renal excretion of potassium:

i. aldosterone ii. increased potassium intake

1. also causes aldosterone release iii. alkalemia iv. increased Sodium delivery to distal tubule v. increased urine flow rate vi. insulin deficiency vii. beta-adrenergic antagonists viii. acidosis – exchange of extracellular H+ for intracellular K+ ix. exercise x. cell lysis


Page 71 of 168 xi. inhibition of Na+/K+ pump

b. Luminal voltage is generally negative, which helps to drive potassium secretion i. aldosterone increases the negative voltage

5. Not an LO, but since most of the packet section is about it… a. Hyperkalemia

i. Signs and Symptoms: 1. ventricular arrythmias 2. cardiac arrest 3. EKG: peaked T waves, increased PR intervals, widened QRS

complexes, sine wave pattern 4. hypotension – because of peripheral vasodilation and decreased

CO 5. weakness and paralysis

ii. compensatory response 1. release of insulin, epinephrine and aldosterone

iii. etiologies: 1. pseudohyperkalemia:

a. faulty blood drawing technique – prolonged tourniquet application or excess activity of arm below tourniquet

b. hemolysis of drawn blood c. lysis of white cells or platelets

2. exogenous potassium load a. from diet, transfusion, or potassium penicillin b. has to be quite a bit for the body to not be able to cope

3. endogenous potassium load or shift a. tissue damage potassium released from intracellular

stores i. tissue damage can be from crush injuries,

rhabdomyolysis (muscle necrosis), ischemia, or intrvascular hemolysis

b. chemotherapy massive cell lysis c. acidemia d. drugs – massive digitalis overdose e. acute hyperosmolality f. hyperkalemic period paralysis (rare)

4. decreased renal potassium excretion from: a. potassium sparing diuretics b. mineralocorticoid deficiency

i. Addison’s Disease ii. Hyporeninemic hypoaldosteronism (type IV

tubular acidosis) iii. Tubular defects of potassium excretion (seen in

sickle cell disease) b. Hypokalemia

i. Signs and Symptoms: 1. muscle weakness, paralysis, necrosis 2. “ileus,” - decreased gut motility

a. because of decreased neuromuscular activity 3. arrythmias

a. especially in digitalized patients 4. glucose intolerance

a. modified insulin secretion


Page 72 of 168 5. impaired renal concentration

a. acquired nephrogenic diabetes insipidus 6. chronic hypokalemia tubular structural abnormalities

ii. Etiology 1. cellular shifts without potassium deficiency

a. alkalosis or hypokalemic periodic paralysis i. unknown origin

2. inadequate intake a. starvation, undernourishment, alcoholism b. kidneys can compensate quite a bit

3. excessive potassium loss a. vomiting, diarrhea b. standard use of diuretics and osmotic diuretics (glucose)

i. this is the most common cause c. primary mineralocorticoid excess (Cushing’s syndrome) d. primary aldosteronism e. Bartter’s syndrome

i. hypokalemia in association with hyperaldosteronism but without hypertension

f. excessive licorice ingestion (umn, what?) g. adrenogenital syndrome h. Liddle’s syndrome

i. stimulation of aldosterone-independent K+ secretion

i. secondary mineralocorticoid excess j. hyperrenimia

i. examples: edematous disorders, malignant hypertension, renovascular hypertension

k. renal tubular acidosis l. antibiotics

i. amphotericin B, gentamicin, carbenicillin m. acute leukemias n. Magnesium deficiency

6. Since the LOs had nothing to do with the lecture, here’s the lecture, just for the hell of it:

a. Case 1: Vomiting patient i. Vomiting loss of fluid renin-angiotensin system is activated to bring

BP back up renin-angiotensin system activates aldosterone promotes Na+ reabsorption, K+ excretion, H+ excretion

1. K+ excretion change is indirect; it is due to the voltage change resulting from Na+ reabsorption: Na+ comes in inside cell is more +, lumen of tubule is more negative lumen attracts cations, therefore K+ and H+ are both pulled out and excreted

ii. H+ excretion results in an increase in bicarb levels (mass action) b. Case 2: Addison’s disease

i. adrenal failure no aldosterone compromised sodium reabsorption 1. Reverse of vomiting situation: Na+ is leaving too much luminal

charge should be too high less K+ and H+ go into lumen K+ and H+ levels in body increase

2. increased H+ decreases bicarb (mass action) c. Case 3: Lung cancer


Page 73 of 168 i. The tumor is inappropriately secreting ADH (SIADH = Syndrome of

inappropriate ADH recretion) 1. Increased ADH increased reabsorption of water osmolality

decreases in spite of normal absolute ionic levels d. Case 4: Diabetes

i. Not shockingly, very high glucose levels are found in the diabetic patient not taking insulin.

ii. other electrolyte/ion levels are all of due to diabetic nephropathy, which is basically the loss of renal function in chronic uncontrolled diabetes.

Block III: Pulm & GI Introduction to respiration and respiratory mechanics I March 20th Dr.Levitzky Overview of the respiratory system, generation of a pressure gradient, elastic properties of the lung and chest wall

1. Exchange of oxygen and carbon dioxide between the body and the atmosphere – related to the metabolism of body tissues

a. Air is breathed in (21% oxygen) through conductive airways into lungs into venous blood that has returned from body tissues (mixed venous blood has high carbon dioxide and low oxygen content –when blood leaves the lungs –arterial blood-- the oxygen content is high and the carbon dioxide is low) into tissue release oxygen into tissue & pick up carbon dioxide in blood back to lungs breathed out

2. Generation of the pressure gradient between the atmosphere and the alveoli a. Air moves from high pressure to low pressure – just like fluid b. Inspiratory muscles contract Thorax volume increases increase transmural

pressure gradient increase alveoli volume pv is static so increased V decreases pressure

c. Transmural pressure is inside-outside, or, here, alveolar-atmospheric d. Δp=VR

i. Translation: change in pressure = volume X resistance 3. Structure of the respiratory system – anatomical and respiratory gases

a. Air goes through nose or mouth pharynx larynx tracheobronchial tree: Trachea Bronchi Bronchioles Terminal bronchioles Respiratory bronchioles Alveolar ducts Alveolar sacs

i. Trachea to terminal bronchioles are “conducting zone” ii. Respiratory bronchioles and distal are “respiratory zone”

b. The conducting zone is anatomical dead space – i.e., no air exchange c. The respiratory zone has gas exchange across the alveoli

4. Elastic properties of lung and chest wall a. Lung distends easily at decreased transpulmonary pressures and not as easily at

increased pressures b. Hysteresis: The fact that the lung distends differently during inspiration and

expiration c. Compliance = Δv/Δp

i. Compliance is the inverse of elastic recoil ii. Compliance is added directly in parallel iii. Compliance is added inversely in series


Page 74 of 168 d. Lungs are in series with chest wall e. Lungs are in parallel with each other f. Elastic recoil of lung: parenchyma has elastic properties, surface tension also helps

(surface tension occurs at any gas-liquid-interface) 5. Passive expansion and recoil of alveoli

a. Alveoli only expand passively in response to contraction of inspiratory muscles, which increases the transmural pressure gradient opens alveoli lowers alveolar pressure

b. Alveolar recoil initiates expiration lung decreases its volume 6. Mechanical interaction of lung and chest wall – related to negative intrapleural

pressure a. Lung decreases its volume due to alveolar elastic recoil b. Chest wall increases its volume from its own outward elastic recoil c. Chest wall holds alveoli open in opposition to their elastic recoil d. Intrapleural pressure becomes more negative because pv is constant, so when the

chest wall pulls out and the alveoli pull in, the intrapleural space increases, so volume has increased and therefore pressure must decrease

7. Pressure-volume characteristics of lung and chest wall – predict changes in lung and chest wall compliances and explain how the combination of the two changes in different physiological and pathological conditions

a. This has really been addressed already. b. Volume is correlated indirectly with pressure (see 8) c. Obstructive diseases increase compliance volume/pressure curve – slope

increased d. Restrictive diseases decrease compliance

8. Draw a normal pulmonary pressure volume curve – label inflation and deflation limbs – cause and significance of hysteresis in the curves

a. Surfactant causes hysteresis

9. Lung compliance calculation; 2 clinical conditions that change compliance

a. Compliance = Δv/Δp b. 1/Total compliance = 1/compliance of the lung + 1/compliance of the chest wall c. Obstructive and restrictive diseases have already been covered.


Page 75 of 168 10. Roles of surface tension, pulmonary surfactant, alveolar interdependence in recoil

and expansion of lung a. If surface tension were constant, small alveoli would have greater pressure because

radius is lower so in order for tension to be maintained, pressure would have to be higher as per LaPlace’s Law:

i. Tension = pressure X radius /2 b. If there were greater tension in the alveoli, you would expect that the alveoli would

collapse c. Luckily for us, surfactant and water have different properties: Surfactant does not

have a constant surface tension i. Surfactant has low surface tension in small areas and high surface tension in

bigger areas equalizes pressure between alveoli of varying sizes ii. Surfactant decreases surface tension decreases inspiratory work

decreases elastic recoil & increases compliance iii. Premature babies sometimes cannot produce surfactant increased

respiratory work collapsed alveoli “Infant respiratory distress syndrome”

iv. In adults – decreased surfactant production and increased surfactant production – “Adult respiratory distress syndrome” aka “Shock-lung syndrome”

d. In addition, we have structural interdependence which helps maintain alveoli in the beautiful honeycomb shape

i. Alveoli help keep each other open via mechanical force ii. Pneumothorax interrupts interdependence lose interdependence

lung collapses 11. FRC – define, and predict changes in FRC in different physiological and

pathological conditions a. FRC is functional residual capacity:

i. =Residual Volume + Expiratory reserve ii. the balance between outward chest and inward lung elastic recoils

determines FRC b. Supine reduces FRC

i. Because lung compliance remains the same but the chest wall compliance decreases substantially in the absence of gravitational force

ii. While standing, gravity pulls abdominal contents farther away allows diaphragm to move farther down. While lying down, abdominal contents, no longer being pulled away from the diaphragm, smush into the diaphragm, preventing the diaphragm from fulfilling its true manifest destiny during inspiration. It makes sense then that the chest wall compliance would go down because theoretically, if your chest wall compliance did not reduce to go along with the diaphragm’s reduced ability to move away from the thorax, then you could just inhale infinitely and rip your chest wall straight off of your diaphragm. Better to just be reined in by the diaphragm’s limitations, n’est-ce pas?

c. Being obese, pregnant, out of the earth’s field of gravity, or having a restrictive disease reduces FRC

i. Think of it as losing your gravity, and see 11-b-ii ii. It restricts your ability to breathe in

d. Emphysema, COPD, chronic bronchitis, asthma (all obstructive diseases) increases FRC

i. You’re having trouble breathing out, so more air gets stuck inside


Page 76 of 168 Respiratory Mechanics II: Respiratory muscles, resistance to air flow, work of breathing March 20th Dr.Levitzky

1. Diagram lung volume, tracheal pressure, alveolar pressure, pleural pressure – during

normal quiet breathing cycle. Identify onset and cessation of inspiration, and cessation of expiration. Relate the pleural and airway pressure values to the movement of air.

2. Definition of airway resistance; factors contributing to or altering air-flow resistance.

a. Resistance = Difference in Pressures / Flow b. 80% of Resistance encountered is airway resistance, c. 20% is pulmonary tissue resistance

i. caused by friction encountered as pulmonary tissues move against each other during expansion

d. Most air flow in the lungs is turbulent or transitional because of extensive branching e. Smaller airways increased total cross-sectional area decreased resistance

i. Cross sectional area is inversely proportional to resistance ii. Poiseille’s Law: (Shout out to Dr.Johnson)

1. R=8X η X length/πr4


Page 77 of 168 3. Dynamic compression of airways during forced expiration, identifying relevant

pressure that drives expiratory flow; describe conditions necessary for dynamic compression to exist. How and where dynamic compression might occur during inspiration.

a. During forced expiration increase intrapleural pressure b. Dynamic compression: compression of the airway during expiration c. Equal pressure point hypothesis: There is a point along the airway where the

transmural pressure = 0 (because the pressure inside = pressure outside) and that when the pressure outside is higher than the equal pressure point collapse of airway in the absence of cartilage

i. During passive expiration, EPP is in cartilage – no collapse ii. During forced expiration, contraction of expiratory muscles increased

alveolar pressure and significantly increased intrapleural pressure (superatsmopheric) causes EPP to be driven farther down into bronchial tree collapse

d. This should not happen during inspiration – we don’t know what disease that would be, but it would suck.

4. Areas of pressure-dependent and –independent portions of flow-volume diagram and explain the shift in the shape of flow-volume curves, which occur with asthma.

a. Flow-volume curve: i. At high lung volumes, the air-flow rate is effort-dependent ii. Effort-independent flow: During forced expiration, at low lung volumes

(less than 80% of TLC), and intrapleural pressure is positive, heterogenous expiration efforts ultimately merge into the same flow curve – it is therefore effort independent

iii. It makes sense that a change in effort will change expiration more when there is greater lung volume to be expelled. At low volumes, you are expiring in vain.

iv. At high enough intrapleural pressure, dynamic compression occurs, which traps gas harder expirations can’t expell gas that’s trapped (Fig 2-22).

b. In restrictive diseases, reduced lung volumes Should decrease peak expiratory flow, because TLC is reduced

i. Effort-independent portion of the curve is normal 1. FEV1/FVC ratio is normal or high because both of these values

are decreased c. In obstructive diseases such as asthma TLC is increased Residual volume may

be greatly increased i. Effort-independent portion of the curve is depressed inward; flow rates are

low for any relative volume ii. Increased resistance small peripheral airway narrowing and reduced gas

flow 5. Relate changes in the dynamic compliance of the lung to alterations in airway

resistance a. Dynamic compliance is the change of volume in the lungs divided by the change in

alveolar distending pressure over the course of a breath b. Dynamic compliance = static compliance at 15 or fewer breaths/minute or even

while a healthy person is breathing faster c. Dynamic compliance/Static compliance ratio decreases in obstructive disease (i.e.,

small airways disease) changes in dynamic compliance therefore reflect changes in airway resistance and changes in the compliance of the alveoli


Page 78 of 168 d. An increase in airway resistance means that the portion of the lung that airway

serves will fill more slowly than it otherwise would i. If the person is breathing quickly, the inability to fill rapidly enough will

reduce the number of alveoli that can be filled during inspiration. ii. Resistance therefore decreases dynamic compliance and decreases oxygen

intake during rapid breathing 6. Factors contributing to the work of breathing

a. Work done in breathing is proportional to ΔpΔv b. Δv= Tidal volume c. Δp= Change in transpulmonary pressure necessary to overcome the elastic and

resistive work of breathing d. The main components of the work of breathing:

i. Elastic recoil of lungs ii. Elastic recoil of chest wall iii. Resistance to air flow

7. Predict alterations in the work of breathing in different physiological and pathological states

a. Obesity i. Increased chest wall elastic recoil Increased work of breathing

b. Restrictive diseases, pulmonary fibrosis or Lack of surfactant i. Increased alveolar recoil increased work

c. Obstructive diseases, asthma, emphysema, bronchitis i. Increased airway resistance ii. Dynamic compression of the alveoli (unopposed) Decreases alveolar

elastic recoil decreased expiratory pressure gradient Alveolar Ventilation: Dead Space, Regional Distribution of Ventilation 3/21/06, Levitzky

1. Define partial pressure and fractional concentration as they apply to gases in air. a. Dalton’s Law: partial pressure of a particular gas is equal to its fractional

concentration times the total pressure of all the gases in the mixture. i. Pgas= % total gas X Ptot

2. List normal atmospheric, inspired, alveolar, and expired values for O2, CO2, and N2 (all listed in mmHg, at standard barometric pressure). Explain why the concentrations change as the gases pass through the respiratory system.

a. Atmospheric: O2- 158; CO2- 0.3; N2- 600.6; =760 torr b. Inspired: O2- 149; CO2- 0.3; N2- 564.0; H2O – 47.0 torr =760 torr c. Alveolar: O2- 104; CO2- 40; N2- 569; H2O – 47.0 torr =760 torr d. Expired: O2- 120; CO2- 27; N2- 566; H2O – 47.0 torr =760 torr e. Air is humidified during inspiration gas concentrations are diluted partial

pressures are lower in inspired than atmospheric air i. Apply the formula to atmospheric gases: PIGas= FIGas (PB- PH20) ii. Translation: partial pressure of gas in inspired air is equal to the fractional

concentration of inspired gas times the difference between the barometric pressure and water vapor pressure

f. Alveolar pressures determined by i. Alveolar ventilation ii. Pulmonary capillary perfusion iii. Oxygen consumption


Page 79 of 168 1. 300 ml/min O2 constantly diffused from alveoli pulmonary

capillaries iv. Carbon Dioxide production

1. 250 ml/min CO2 constantly diffused from pulmonary capillaries alveoli

g. Expired air = 350 ml alveolar + 150 ml dead space air i. O2 pressure higher in mixed expired air than alveolar but lower than in

inspired PO2 ~ 120 torr ii. CO2 pressure lower in mixed expired air than alveolar but higher than

inspired PCO2 ~ 27 torr 3. Draw a normal spirogram labeling the four lung volumes and four capacities. List

the volumes which comprise each of the four capacities. Identify which volume and capacities cannot be measured by spirometry

a. Four lung volumes i. Tidal Volume(VT)- 500 ml; a normal breath

ii. Residual Volume(RV)- 1.5 L; what is always left in your lungs so they don’t collapse

iii. Inspiratory Reserve Volume (IRV)- 2.5 L; the extra air you can breathe in with forced inspiration, beginning after tidal volume

iv. Expiratory Reserve Volume (ERV)- 1.5 L; the extra air you can breathe out with forced expiration, beginning after tidal volume

b. Four lung capacities i. Functional Residual Capacity(FRC)= RV+ERV; volume of gas remaining

in the lung after normal expiration ii. Inspiratory Capacity (IC)= VT + IRV; the total inhaled into lungs with

maximal inspiratory effort, beginning at the end of normal tidal expiration iii. Total Lung Capacity (TLC)= VT + IRV + ERV + RV; the total volume of

air in the lungs after a maximal inspiration iv. Vital Capacity (VC)= VT + IRV + ERV; total volume of air that can be

expelled from the lungs in forced expiration following a forced inspiration c. Any volume that includes the residual volume cannot be measured using spirometry.

Therefore, in addition to RV, FRC and TLC cannot be measured directly by spirometry. Vital capacity does not include RV and therefore can be measured by spirometry.

4. Predict the effects of alterations in lung and chest wall mechanics, due to normal or pathological processes, on the lung volumes.

a. Normal Physiological Processes i. Gravity-

1. [Standing Supine] ↓ FRC; abdominal contents no longer being pulled away from diaphragm

2. ↓ FRC ↓ ERV and ↑IRV 3. RV, VC, and TLC may decrease slightly b/c increased blood flow

to the thoracic cavity b. Pathological Processes

i. Restrictive Disease 1. Reduced compliance of lungs compressed lung volumes 2. ↓FRC, TLC, VC, IRV, ERV, and possibly even RV 3. ↓ Tidal volume, VT with corresponding ↑ respiratory rate 4. Example: alveolar fibrosis

ii. Obstructive Disease 1. ↑ resistance to airflow 2. Mucous obstructs airways


Page 80 of 168 3. high intrapleural pressure to overcome airway resistance during

forced expiration 4. big ↑ RV, FRC, TLC 5. ↓VC and ERV 6. ↓ respiratory rate with corresponding ↑VT 7. Examples: emphysema, chronic bronchitis, asthma

5. Define minute ventilation and alveolar ventilation. a. Minute ventilation- amount of air entering and leaving the nose or mouth per minute b. Alveolar ventilation- amount of air entering and leaving the alveoli per minute; less

than the minute ventilation because some of each inspiration remains in the conducting airways and never reaches the alveoli

6. Define the anatomic dead space and relate anatomic dead space and the tidal volume to alveolar ventilation.

a. Anatomic dead space- conducting airways; airways that are too thick for gas diffusion to take place; airways where blood does not come into contact with air

b. On average, 150 ml per tidal volume remains in the anatomic dead space i. VT= VD + VA

ii. Tidal volume is equal to dead space volume plus volume entering and leaving the alveoli per breath

c. When we rearrange the equation in 6.b.i we get the equation for alveolar ventilation: i. A= E - D

ii. represents minute ventilation iii. Translation: Alveolar ventilation is equal to the expired minute volume

(equivalent to tidal volume) minus the volume wasted ventilating the dead space per minute

7. Understand the measurement of the anatomic dead space from the single breath test diagram (See Figure 3-7)

a. Subject breathes in 500 ml test gas (ex. Helium) from a balloon b. Some of that gas goes to alveoli (350 ml), some remains in conducting airways (150

ml) c. The first portion of gas breathed back into the balloon on expiration is undiluted

test gas d. The remainder of the expired gas is diluted test gas, so the total concentration of gas

in the balloon is lower than it was before inspiration e. The last 150 ml that is expired from the alveoli remains in the anatomic dead space

after expiration 8. Determine alveolar ventilation. Describe how alveolar ventilation can remain

constant when minute ventilation changes. a. Alveolar ventilation determined from VT, breathing frequency, and dead space

ventilation

b. Equation from 6.c.i. ( A= E - D) provides the relationship between minute ventilation and alveolar ventilation

i. ↑ ↑Dead space Alveolar ventilation remains constant ii. ↓ ↓Dead space Alveolar ventilation remains constant

9. Define and determine physiologic and alveolar dead spaces. a. Physiologic dead space= anatomic dead space + alveolar dead space b. Alveolar dead space is volume of gas that enters unperfused alveoli no gas

exchange occurs i. Not usually present in healthy individuals


Page 81 of 168 c. Any expired CO2 must have come from alveoli that are ventilated and perfused. In a

healthy individual, this CO2 level should be the same as that in perfused alveoli, alveolar capillaries, and arterial blood. However, if the expired PCO2 (which represents the mixed alveolar PCO2) is much less than the arterial PCO2, this indicates the presence of significant alveolar dead space.

i. Translation: a lot of air is going to alveoli that are not getting perfused, so the total volume of air you breathe out does not have the same CO2 level as the blood perfusing the alveoli

ii. This difference is not surprisingly referred to as the arterial-alveolar CO2 difference. If it is large, it signifies a lot of alveolar dead space.

10. Describe in quantitative terms the effect of ventilation on Pco2 according to the alveolar ventilation equation.

a. PAO2= FIO2 (PB-PH20) - PACO2/R i. FIO2 (PB-PH20)= PIO2 (inspired partial pressure of oxygen)

ii. R= respiratory exchange ratio, CO2/ O2, AKA alveolar ventilation iii. As alveolar ventilation increases, ↓PACO2 (alveolar CO2 pressure) brings

PAO2 (alveolar partial pressure of oxygen) closer to PIO2 (inspired partial pressure of oxygen)

11. Be able to estimate the alveolar oxygen partial pressure, PAO2, using the simplified form of the alveolar gas equation.

a. See above, question 10, for formula… and know how to plug and chug 12. Predict the effects of alterations of alveolar ventilation on alveolar carbon dioxide and

oxygen levels. a. See above, question 10 b. ↑R (alveolar ventilation) ↓ PACO2 brings PAO2 closer to PIO2 c. ↓R ↑PACO2 brings PAO2 further from PIO2

13. Describe the regional differences in alveolar ventilation found in the normal lung and explain these differences.

a. Regional differences in the lung influenced by gravity i. “lower” regions (with respect to gravity) considered “dependent” better

perfusion and better ventilation – therefore more gas exchange. ii. “non-dependent” regions less ventilated and less perfused – therefore less

gas exchange 1. Perfusion is more reduced than ventilation is, therefore the V/Q

ratio is higher in the upper part of the lung b. Dependent (lower) region

i. Less negative (higher) intrapleural pressure ii. Lower transpulmonary pressure (alveolar – intrapleural) at FRC

iii. Alveoli have smaller volume this leads to difference in ventilation! c. Move up lung to non-dependent region more negative intrapleural pressure,

higher transpulmonary pressure, larger volume alveoli 14. Predict the effects of changes in the lung volumes, aging, and disease processes on

the regional distribution of ventilation. a. Aging Increased static lung compliance, decreased chest wall compliance

i. Caused by: 1. loss of alveolar elastic recoil 2. calcification of costal cartilages 3. decreased spaces between vertebrae 4. greater spinal curvature

ii. ↑ FRC, constant TLC


Page 82 of 168 b. ↓alveolar elastic recoil ↓ opposition to dynamic compression airways close at

higher volumes higher closing capacity i. airways in dependent regions close at lung volumes above FRC more

ventilation in non-dependent regions c. ↓ strength of expiratory muscles

i. ↑ RV ii. ↓ maximal expiratory rates (i.e. FEV1)

d. ↓ arterial oxygen tension i. ventilation of poorly perfused areas

ii. loss of alveolar surface area, decreased diffusion capacity e. More mismatch, lower PaO2

15. Define the closing volume and explain how it can be demonstrated. a. Closing volume: lung volume at which airway closure begins to occur b. Use Fowler method to measure closing volume

i. Beginning at RV take a deep inhale (to TLC) of 100% oxygen ii. Subject then exhales to RV, measure nitrogen levels

1. Phase I- subject exhales purely from anatomic dead space; pure oxygen, no nitrogen

2. Phase II- mixture of dead space and alveolar gas, increasing nitrogen levels (nitrogen was in the alveoli from previous breath)

3. Phase III- mixed alveolar gas from upper and lower regions, nitrogen level “plateaus”

4. Phase IV- airways begin to close; lower region, where there is less nitrogen, closes first; nitrogen concentration rises rapidly as more air comes from upper alveoli which have more nitrogen.

16. Predict the effects of changes in pulmonary mechanics on closing volume. a. Airway resistance problems phase III of Fowler test not horizontal

i. alveoli supplied by high-resistance airways fill more slowly than those supplied by normal airways those with higher resistance will get less 100% oxygen during inspiration higher resistance airways have higher nitrogen concentration

ii. Higher resistance airways empty slower on expiration rise in nitrogen comes later in expiration (during phase III)

Pulmonary Blood Flow: Bronchial Circulation, Pulmonary Vascular Resistance, Regional Distribution of Pulmonary Circulation 3/21/06, Levitzky

1. Compare and contrast the bronchial circulation and the pulmonary circulation a. Bronchial circulation, which comes from aorta and intercostal arteries, supplies the

tracheobronchial tree and other structures of the lung down to the level of the terminal bronchioles

i. Distal to bronchioles, supplied by pulmonary circulation (respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli)

ii. Bronchial blood pressure is equivalent to systemic blood pressure because bronchial circulation is part of the systemic circulation

1. pulmonary blood pressure is lower than these two 2. Describe the anatomy of the pulmonary circulation and explain its physiological

consequences a. Thin-walled vessels, little smooth muscle less resistance to flow lower

pressure better gas exchange


Page 83 of 168 3. Compare and contrast the pulmonary circulation and the systemic circulation

a. Pulmonary arteries: i. Thinner walls, less smooth muscle less resistance to flow

ii. lower intravascular pressures more distensible and compressible iii. More susceptible to surrounding pressure changes

4. Describe and explain the effects of lung volume on pulmonary vascular resistance a. ↑ lung volume

i. ↑ alveolar volume pulmonary capillaries elongate and diameter decreases ↑ resistance in alveolar vessels

ii. intrapleural pressure more negative ↑transmural pressure gradient ↑distention of vessel ↑ radial traction ↓ resistance in extraalveolar vessels

iii. REMEMBER: resistance is inversely related to radius to the 4th power b. ↓ lung volume

i. intrapleural pressure more positive extraalveolar vessels compressed ↓ radial traction ↑ resistance in extraalveolar vessels

1. Traction: elastic recoil of alveoli has a secondary effect of pulling the adjacent airways open, preventing airway collapse

c. Alveolar and extraalveolar vessels can be visualized to be in series, so their resistances are additive changes in both types of vessels gives total PVR (see Fig. 4-4)

i. At low and high lung volumes ↑PVR 5. Describe and explain the effects of elevated intravascular pressures on pulmonary

vascular resistance (PVR) a. ↑ intravascular pressure ↓ PVR

i. ↑ CO pulmonary artery pressure is fairly constant due to ↓ PVR ii. this decrease appears to be passive (no neural nor humoral influence)

iii. due to recruitment and distention b. Recruitment

i. ↑ pulmonary pressure critical opening pressure met for previously unopened vessels new parallel pathways open ↓ PVR

c. Distention i. ↑ pulmonary pressure ↑ transmural pressure gradient of pulmonary

vessels distention of vessels ↑ vessel radius ↓ PVR 6. List the neural and humoral factors that influence pulmonary vascular resistance

a. Increase PVR: (mnemonic = SANTAH LAP, do you like santah’s lap?) i. Sympathetic innervation (S)

ii. α-Adrenergic agonists (A) iii. Norepi, epi (N) iv. Thromboxane (T) v. Angiotensin (A)

vi. Histamine (H) vii. Low pH if mixed venous blood, blood returning from the heart (L)

viii. Alveolar hypoxia or Hypercapnia (A) ix. PGF2α, PGE2 (P)

b. Decrease PVR: i. Parasympathetic innervation

ii. Acetylcholine iii. β-Adrenergic agonists iv. PGE1 v. Prostacyclin (PGI2)


Page 84 of 168 vi. Nitric oxide

vii. Bradykinin 7. Describe the effect of gravity on pulmonary blood flow

a. Lower parts of the lung (gravity dependent) better perfused (more pulmonary blood flow) than upper parts of lung

8. Describe the interrelationships of alveolar pressure, pulmonary arterial pressure, and pulmonary venous pressure and their effects on the regional distribution of pulmonary blood flow.

a. When alveolar pressure (PA) ≥ pulmonary arterial pressure (Pa), perfusion of the lung stops. The lung is divided into zones based upon this relationship and their relationship to pulmonary venous pressure (PV)

b. Zone 1 i. The highest (gravity-independent) portion of the lung

ii. PA> Pa> PV Pressure in the alveoli exceeds pressure in the arterioles, so there is no blood flow into the alveoli

iii. Alveolar dead space (i.e. ventilated but not perfused) iv. In healthy individuals not present, even at rest

c. Zone 2 i. The middle portion of the lung

ii. Pa> PA> PV Now pressure in the arterioles exceeds pressure in the alveoli, and the effective driving pressure into the alveoli is Pa- PA

iii. Driving pressure ↑ in lower lung iv. Ventilated and perfused

d. Zone 3 i. The bottom portion of lung

ii. Pa> PV> PA Pressure in the arterioles still exceeds that of the alveoli, but now pressure in the venules also exceeds that in the alveoli. Blood flow continues, but now the effective driving pressure is Pa- PV

iii. Driving pressure remains fairly constant as move down the lung b/c hydrostatic pressure of arteries= that of veins

iv. Ventilated and perfused 9. Predict the effects of alteration in alveolar pressure, pulmonary arterial and venous

pressure, and body position on the regional distribution of pulmonary blood flow. a. ↑ Zone 1 area

i. Alveolar pressure changes with each breath, even more so with speech, exercise, etc.

ii. A positive end expiratory pressure (PEEP) ventilator ↑alveolar pressure iii. Hemmorrhage ↓ pulmonary blood flow and pressure iv. General anesthesia ↓ pulmonary blood flow and pressure

b. ↑ Zone 2 area recruit Zone 1 to Zone 2 i. ↑CO

ii. ↑ pulmonary artery pressure c. Changes in body position alter orientation of zones

i. Zones retain same relationship with respect to gravity 10. Describe hypoxic pulmonary vasoconstriction and discuss its role in localized and

widespread alveolar hypoxia. a. Hypoxic pulmonary vasoconstriction (that’s right, HPV) diverts venous blood flow

away from poorly ventilated areas by locally increasing vasoconstriction. b. Localized atelectasis or obstruction of an airway localized HPV (just where the

obstruction is)


Page 85 of 168 c. Hypoxia of entire lung HPV throughout entire lung ↑pulmonary artery

pressure recruit unperfused capillaries ↑ gas exchange d. HPV Mechanism: Hypoxia decreases outward potassium current pulmonary

vascular smooth muscle depolarizes calcium enters contraction 11. Describe the causes and consequences of pulmonary edema.

a. Causes i. ↑ permeability of pulmonary capillary endothelium

ii. ↑ capillary hydrostatic pressure iii. ↓ interstitial hydrostatic pressure iv. ↑ reflection coefficient v. ↓ capillary colloid osmotic pressure

vi. ↑ interstitial colloid osmotic pressure vii. lymphatic insufficiency

viii. other conditions: head injury, heroin overdose, high altitude b. Consequences

i. diffusion of gases (particularly oxygen) decreases Ventilation-Perfusion Relationships The VA/Q concept; shunt; Physiological Dead Space; Regional Distribution of VA/Q March 22nd, 2006 Levitzky

I. Predict the consequences of mismatched ventilation and perfusion a. Understanding Ventilation-Perfusion relationships (VA/QC)

i. Va/Qc and V/Q are interchangeable. Don’t stress. i. For optimal gas transfer to occur in the lung, ventilation and perfusion

must match ii. VA = alveolar ventilation, QC = perfusion (flow through alveolar capillary) iii. Alveolar ventilation is about 4-6 L/min and pulmonary blood flow (which

is equal to cardiac output) has a similar range V/Q for whole lung = 0.8 to 1.2

1. However, V and Q must be matched on the alveolar-capillary level and the V/Q for the whole lung is really of interest only as an approximation of the situation in all the alveolar-capillary units of the lung

2. If V/Q = 1.0, gas exchange is optimal 3. V/Q = 0 – no gas exchange because you’re not breathing 4. V/Q = ∞ – no gas exchange because you’re not bleeding… er, not

perfusing. In fact, maybe you are bleeding, profusely. iv. Local airway responses and hypoxic pulmonary vasoconstriction (HPV)

help match ventilation and perfusion so that gas exchange can occur b. Consequences of high and low V/Q

i. Normal V/Q = .8 1. Inspired air entering alveoli: PO2 = 150 mmHg; PCO2=0 mmHg 2. Mixed venous blood entering pulmonary capillaries: PO2 = 40

mmHg; PCO2 = 45mmHg 3. When inspired air mixes with the air already in the lungs, the partial

pressure gradients of oxygen and carbon dioxide change PO2 becomes 100, PCO2 becomes 40

4. The partial pressure gradient for O2 and CO2 diffusion from alveolus to pulmonary capillary = the difference between the partial pressure in the alveoli and in the mixed venous blood:


Page 86 of 168 a. For oxygen coming in, about 100-40 = 60 mmHg; for CO2

going out about 45-40 = 5 mmHg 5. Result Alveolar and pulmonary capillary blood leaving lungs

have equal partial pressures of gas; for both: PO2 = 100 mmHg; Alveolar PCO2 = 40mmHg

ii. Low V/Q If V/Q in an alveolar-capillary unit decreases, gas exchange will become more efficient Alveolar PO2 will therefore fall, and alveolar PCO2 will rise, (i.e., instead of oxygen falling in the blood, it falls in the alveoli at first)

1. Extreme case perfusion, but no ventilation as in completely occluded airway V/Q = 0 air trapped in alveolus equilibrates by diffusion with gas dissolved in mixed venous blood entering capillary-alveolar unit no gas exchange occurs, any blood perfusing this alveolus will leave it exactly as it entered it leads to intrapulmonary shunt

a. Result PAO2 = 40 mmHg; PACO2 = 45 mmHg iii. High V/Q If V/Q in alveolar-capillary unit increases, gas exchange will

become less efficient, as the ventilation is now perfusion limited Alveolar PO2 will rise, and alveolar PCO2 will fall

1. Extreme case ventilation, but no perfusion as in blocked blood flow by pulmonary embolism V/Q = ∞ No gas exchange into or out of blood can occur because blood is not perfusing the alveoli Gas composition of unperfused alveolus is the same as that of inspired air Alveolar dead space

a. Result Alveolar PO2 = 150 mmHg; Alveolar PCO2 = 0 mm Hg

b. If this alveolar-capillary unit were unperfused because alveolar pressure exceeded capillary pressure (rather than because of an embolus), Zone 1

iv. There is a continuum of V/Qs ranging from 0 to ∞, resulting in a range of PO2s and PCO2s, the ventilation-perfusion ratio line, as shown on the O2-CO2 diagram (p. 116, Figure 5-2)

1. LOW V/Q relatively LOW PO2s and HIGH PCO2s 2. HIGH V/Q relatively HIGH PO2s and LOW PCO2s

II. Describe the methods used to assess the matching of ventilation and perfusion a. Testing for Mismatched Ventilation & Perfusion

i. Includes calculations of 1. the physiologic shunt 2. physiologic dead space 3. alveolar-arterial oxygen difference 4. single breath carbon dioxide test 5. lung scans after inhaled and I.V. administered marked Xe and Tc 6. Multiple inert gas elimination technique

ii. R to L shunt is the mixing of venous blood that has not been fully oxygenated into the arterial blood

1. Dead space is ventilation without perfusion. Shunts are perfusion without ventilation.

2. The intrapulmonary shunts can be absolute shunts or they can be “shunt-like” states, that is, areas of low V/Q ratios in which alveoli are underventilated and/or overperfused

3. Physiologic Shunt = Anatomic Shunt + Intrapulmonary Shunt


Page 87 of 168 iii. Physiologic Shunts present when the V/Q is less than 1 There is low

alveolar PO2, which causes a low PO2 and Hb saturation in the blood leaving this area of the lungs. When this blood mixes with blood from better ventilated areas, it produces a decrease in the overall arterial PO2 and content

1. Anatomic Shunts consists of systemic venous blood entering the L ventricle without having entered the pulmonary vasculature. In a healthy person, about 2-5% of the cardiac output enters the left side of the circulation directly without passing through the pulmonary capillaries (includes venous blood from bronchial veins, thebesian veins, which supply the myocardium, and pleural veins)

a. Pathologic anatomic shunts include R to L intracardiac shunts, as in tetralogy of Fallot

2. Absolute Intrapulmonary Shunts Mixed venous blood perfusing pulmonary capillaries associated with, like, totally unventilated or collapsed alveoli constitutes an absolute shunt no gas exchange occurs as the blood passes through these parts of the lung referred to as true shunts

a. V/Q = 0 in a true shunt 3. Shunt-like States alveolar-capillary units with low V/Q ratios,

act to lower the arterial PO2 because blood draining these units has a lower PO2 than blood from units with well-matched V and Q

4. The Shunt equation conceptually divides all alveolar-capillary units into those that have well-matched V/Q and those with V/Qs approaching 0 Shunt equation combines areas of absolute shunt and shunt-like areas The resulting ratio of shunt flow to the cardiac output is referred to as the venous admixture 3. Venous admixture the part of cardiac output that would

have to be perfusing absolutely unventilated alveoli to cause the systemic arterial O2 content obtained from a patient

4. Pulmonary venous admixture (SHUNT EQUATION)

Qs/Qt = ( CcO2 - CaO2)/( CcO2 - CvO2)

Qs = amount of blood flow per minute entering the systemic arterial blood without receiving any O2 (shunt flow) Qt = total pulmonary blood flow per minute (CO) Cc′O2 = End capillary O2 content CaO2 = arterial O2 content C⎯⎯v O2 = O2 content of the mixed venous blood

• The shunt equation is multiplied by 100 so that shunt flow is expressed as % of cardiac output

5. CaO2v &C⎯⎯v O2 can be measured from blood samples 6. O2 content of blood at end of pulmonary capillaries with well-

matched V/Q ratios (Cc′O2) must be calculated using the alveolar air equation and the patient’s Hb concentration

7. At LOW inspired O2 concentrations, Qs/Qt will include both true shunts and alveolar-capillary units with low V/Q

1. After patient has inspired 100% O2 for 30 minutes, even alveoli with low V/Qs will have high enough


Page 88 of 168 alveolar PO2s to completely saturate the Hb in the blood perfusing them

2. These units will no longer contribute to the calculated Qs/Qt and the new calculated shunt should include only areas of absolute (true) shunts

8. At HIGH inspired O2 concentrations, atelectasis may occur in otherwise very poorly ventilated alveoli that remain perfused, and so by asking a patient with restrictive disease to inspire high O2, in order to assess how much blood is being oxygenated vs. physiologically shunted, you may in fact be altering what you were trying to measure because the FIO2 is so high (results may be skewed towards the shunt seeming larger than it really is)

b. Physiologic dead space = anatomic dead space + alveolar dead space i. Anatomic dead space (VD) volume of gas that occupies “conducting

zone” i.e., the airways, which do not participate in gas exchange ii. Alveolar dead space alveolar-capillary units with V/Q = ∞, no blood

flow, and therefore no gas exchange – this occurs in pulmonary embolism 1. Alveolar dead space arterial-alveolar CO2 difference

a. the end tidal PCO2 is normally equal to the arterial PCO2, but: alveolar dead space CO2 cannot diffuse out of blood into alveoli CO2 cannot be expired raising arterial PCO2 arterial PCO2 greater than the end tidal PCO2

2. The Bohr equation is used to determine the physiologic dead space by determining CO2 tensions in expired and alveolar gases…

VV

P P

Pd

T

a E

a

CO CO

CO

=−

2 2

2

• Arterial CO2 (PaCO2) almost always = Alveolar CO2 (PACO2) • PECO2 = CO2 tension in mixed expired air • PACO2 = CO2 tension in alveolar gas (estimated by end tidal

samples) • Increase in dead space lower CO2 tension in expired air

greater ratio of dead space to minute ventilation c. Alveolar-arterial O2 difference The difference or gradient between the partial

pressure of O2 in the alveolar spaces and the arterial blood v. Normally, 5-15 mm Hg (represents mismatch between arterial and

alveolar pressure) 1. factors include normal anatomic shunt, some degree of V/Q

mismatch, and diffusion limitation in some parts of the lung vi. Larger-than-normal differences between alveolar and arterial PO2,

indicate significant V/Q mismatch vii. May also be caused by anatomic or intrapulmonary shunts, diffusion

block, low mixed venous PO2s, breathing higher than normal O2 concentrations, or shifts of the oxyhemoglobin dissociation curve (p., 180, Table 8-6)

d. Single-breath CO2 test: i. Expired concentration of CO2 can be monitored to determine V/Q

mismatch ii. Patient inspires and then exhales to end-tidal volume, and a plateau of

expired CO2 is recorded


Page 89 of 168 1. expired air is (in this order):

a. air from the anatomic dead space b. mixed alveolar and anatomic dead space air c. gas from all the ventilated alveoli (which have CO2 in them

to be expired) iii. V/Q mismatch is observed if regions of lung empty asynchronously

e. Lung scan of inhaled and injected radioactive markers can be used to inspect the location and amount of ventilation and perfusion to the various regions of the lung

f. Multiple Inert Gas Elimination Technique Elimination via the lungs of different gases dissolved in the mixed venous blood is affected differently by variations in the ventilation-perfusion ratios of alveolar-capillary units, according to the solubility of each gas in the blood

i. Gases with low solubility in the blood would be retained in the blood only by units with very low (or zero) V/Qs

ii. Gases with high solubility in the blood would be eliminated mainly in the expired air of units with very high (like maybe 10) V/Qs

iii. Mixture of 6 gases dissolved in saline infused into peripheral vein at 2-5mL/min until steady state of gas exchange is established (about 20 minutes)

1. Samples of expired air are collected along with measurements including cardiac output by indicator dilution, minute ventilation, and arterial and MVB gases

2. In a young healthy patient at rest, V/Q is consistently near 1, with some range. Having units with a V/Q <0.3 or >3.0 is extremely unusual.

3. A middle-aged healthy person, there is a wider dispersion of V and Q, with more units with ratios >3.0 and to units with ratios <0.3

4. See Levitzky’s 5-5 for a graph III. Describe the methods used to determine the uniformity of the distribution of the

inspired gas and pulmonary blood flow a. Non-uniform gas distribution Non-uniform ventilation of the alveoli can be

caused by uneven resistance to airflow or nonuniform compliance in different parts of the lung

i. Uneven resistance to airflow result of collapsed airways (e.g. emphysema); bronchoconstriction (e.g. asthma); decreased lumen diameter due to inflammation (e.g. bronchitis); obstruction by mucus; compression by tumors of edema

ii. Uneven compliance result of fibrosis, regional variations in surfactant production, pulmonary vascular congestion or edema, emphysema, atelectasis, pneumothorax, compression by tumors or cysts

1. Single-breath-of-O2 test Monitor expired N2 concentration in "alveolar plateau" phase (p.80, Figure 3-14). Steep plateau = non-uniform gas distribution.

a. In a healthy person, the slope of phase III is nearly horizontal. To review what phase III means (also discussed in 3/21 notes) here is a picture.


Page 90 of 168 I. S

ee notes for March

II. b. In those with areas of increased airway resistance, phase

III slope is steep alveoli supplied by high-resistance airways fill more slowly than those supplied by the normal airways during the 100% O2 inspiration These alveoli have a higher N2 concentration Over the course of one expiratory effort, as the varyingly supplied alveoli empty at different rates, oxygen concentration of expired air will decrease and nitrogen concentration of expired air will increase, as the source of expired air shifts from “faster” to “slower” alveoli

2. Nitrogen-Washout Test Patient breathes 100% oxygen and the expired N2 concentration is monitored over a number of breaths. With successive respirations, expired end-tidal N2 concentration falls as N2 is “washed” out of the lung

a. Patients with normal distribution of airways resistance will reduce their expired end tidal N2 concentration to less than 2.5% within 7 minutes

b. Patients breathing normally who take more than 7 minutes to reach an alveolar N2 concentration of less than 2.5% have high resistance pathways, or “slow alveoli”

3. Trapped Gas Differences between the FRC determined by helium-dilution technique and the FRC determined using a body plethysmograph may indicate gas trapped in the alveoli because of airway closure

4. Radioactive Markers Patients take breath of 133Xe or 99mTc DTPA and oxygen mixture, and a picture of the whole lung is taken with a scintillation counter to indicate which regions of the lung are poorly ventilated

iii. Nonuniform Distribution of Pulmonary Blood Flow embolization or thrombosis; compression of pulmonary vessels by high alveolar pressures, tumors, exudates, edema, pneumothorax, hydrothorax; destruction or


Page 91 of 168 occlusion of pulmonary vessels, pulmonary vascular hypertension, or collapse or overexpansion of alveoli

1. These tests indicate the locations of relatively large regions of poor perfusion…

1. Pulmonary angiograms 2. Lung scan after injection of 131I or technetium labeled

macroaggregates of albumin 3. Lung scan after intravenous 133Xe

IV. Explain the regional differences in the matching of ventilation and perfusion of the normal lung a. See LOs from 3/21

V. Predict the consequences of the regional differences in the ventilation and perfusion of the normal upright lung a. See LOs from 3/21

VI. Classify and explain the causes of tissue hypoxia a. Hypoxia inadequate O2 supply to the body tissues. Disease processes can

severely limit the O2 supply anywhere between the atmosphere and the body’s cells. Hypoxia occurs “downstream” of the limitation (i.e. toward the cells); a normal O2 tension may be present “upstream” (i.e. toward the environment)

b. Types of Hypoxia i. Arterial hypoxia inadequate oxygenation of the arterial blood, caused by

breathing gas with a low O2 tension or by pathology 1. Hypoventilation reduces alveolar and arterial O2 tensions,

increases the alveolar and arterial CO2 tensions Hypercapnia 2. Diffusion limitation reduction in diffusing capacity of lung

secondary to pulmonary disease that prevents equilibration between O2 tension in alveoli and pulmonary capillaries

3. Physiologic shunts (V/Q ratio imbalances) produce low O2 tensions in the areas of the lung with low V/Q ratios

a. V/Q imbalance is by far the most common cause of hypoxia

b. Administration of 100% O2 to affected patients can correct hypoxia because O2 flushes N2 from alveoli, and alveolar O2 tension, even in low V/Q areas will rise to functional levels

4. Anatomic Shunts mixing of true venous blood and arterial (oxygenated) blood diluting normal O2 concentration

a. Arterial O2 tension reduced in proportion to the fraction of cardiac output that is shunted Normal individuals have an anatomic shunt of less than 5% of cardiac output

ii. Ischemic hypoxia inadequate blood flow 1. Reduced blood flow may involve entire body (e.g. congestive heart

failure) or localized area (e.g. arteriosclerosis) 2. Atherosclerosis most common cause of arterial obstruction

increases local vascular resistance and reduced blood flow 3. Decreased O2 delivery to tissue infarction and dysfunction 4. Arterial O2 tension and content may be normal, but tissues

withdraw large amounts of O2 from capillary blood as a result, venous O2 content is reduced

iii. Anemic Hypoxia insufficient amount of functional Hb


Page 92 of 168 1. May be caused by deficiency of nutrients (e.g. iron, B12) or due to

blood loss or large amounts of methemoglobin or carboxyhemoglobin

2. ↓ O2 capacity ↓ O2 content iv. Histotoxic Hypoxia inactivation of certain metabolic enzymes (e.g.

cytochromes) and by chemical poisons (e.g. cyanide) 1. Tissues unable to use O2, as a result, venous O2 tension and

content are high Diffusion Fick’s Law of Diffusion; Hypoxia; Diffusion Capacity of the Lung; Diffusion v. Perfusion Limits to Gas Transfer March 22nd, 2006 Levitzky

I. Diffusion vs. “bulk flow” a. Diffusion is net flow down a concentration gradient

i. Faster at higher temperatures ii. Net movement of a gas is always down the partial pressure gradient for that

gas iii. The blood must be exposed to a partial pressure for a finite time for gas to

equilibrate between the gas and liquid phases. 1. The time required for equilibration is a function of the contact area

between the liquid and the gas (surface area), the solubility and diffusion properties of the gas, and the diffusion gradient

2. Physiologic, resting time spent in pulmonary capillaries for each RBC is 0.75 – 1.25 seconds

b. Gas moves through airways by bulk flow until it reaches the terminal bronchioles diffuses into pulmonary capillaries bulk flow though pulmonary veins diffusion out of arterial blood into tissue, and from tissue into venous blood moves by bulk flow from the capillary beds to the pulmonary vasculature diffuses from venous blood into alveoli expired by bulk flow

II. State Fick’s Law for Diffusion a. Fick’s Law defines the rate of pulmonary gas diffusion (i.e. the volume of gas per

minute that crosses the alveolar-capillary membrane):

Vgas = gas flow (mL/min) A = area T = thickness D = diffusivity P1 – P2 = partial pressure gradient

The rate of gas moving across a membrane is directly proportional to the surface area of the sheet, the diffusivity, and the difference in gas concentration between the two sides, but is inversely proportional to the membrane thickness.

b. The potential surface area (A) of the blood-gas barrier is 70m2 in an average healthy adult at rest

i. ↑ capillary recruitment, as in exercise, ↑ surface area ii. ↓venous return, as in hemorrhage or ↑alveolar pressure by

PEEP capillaries may be derecruited and ↓surface area available for diffusion


Page 93 of 168 c. Thickness (T) of the alveolar-capillary diffusion barrier = 0.2 – 0.5 μm

i. This can increase in interstitial fibrosis or edema d. Diffusivity, or diffusion constant (D), for a gas is directly proportional to the

solubility of the gas in the diffusion barrier and is inversely proportional to the square root of the molecular weight (MW) of the gas:

i. The solubility of CO2 in the liquid phase is 24 times that of O2, and diffuses

about 20 times more rapidly though the alveolar-capillary barrier than does O2

1. patients develop problems in O2 diffusion before CO2 diffusion retention problems

III. Distinguish between perfusion limitation and diffusion limitation of gas transfer in the lung a. Limitations of gas transfer the partial pressure of a gas in the mixed venous

blood and in the pulmonary capillaries is just as important as the alveolar partial pressure in determining its rate of diffusion

i. Summary of gas transfer limitations 1. If partial pressure of a gas in the plasma equilibrates with the

alveolar partial pressure of the gas within the amount of time the blood is in the pulmonary capillary perfusion limited

a. Example: Nitrous oxide (N2O), which dissolves into blood and is not taken up by any carriers, therefore exerting its full partial pressure, diminishing its partial pressure gradient for that unit of blood and forcing it to wait for new blood in order to continue diffusing

2. If equilibration does not occur within the time the blood is in the capillary diffusion limited

a. Example: Carbon monoxide, which binds to Hb and therefore does not exert its partial pressure, allowing it to keep diffusing as fast as it is able to diffuse given its own properties and those of the capillaries

IV. Describe the diffusion of O2 from the alveoli into the blood a. Gas moving from alveolus to blood must pass through: pulmonary surfactant

Alveolar epithelium Interstitium Capillary endothelium Plasma RBC membrane to reach Hb

b. Oxygen O2 binds to Hb and exerts no partial pressure in pulmonary capillary blood, so the partial pressure gradient is well maintained across the alveolar-capillary membrane O2 transfer occurs

i. Diffusion of O2 normal alveolar PO2 is 100 mm Hg, blood entering the pulmonary capillary has a PO2 of 40 After dissolving across the alveolar-capillary membrane, the O2 diffuses into the plasma, raising the plasma O2 tension O2 then diffuses into the RBC where it combines with Hb

ii. The binding of O2 to Hb occurs within 0.01s, and at normal alveolar partial pressure of O2, Hb becomes saturated very quickly Thus, the partial pressure of O2 in the blood rises to that in the alveolus, and from that point, no further O2 transfer occurs

iii. Under normal alveolar PO2 and a normal resting cardiac output O2 transfer from alveolus to pulmonary capillary is perfusion-limited


Page 94 of 168 iv. During exercise ↑ CO blood spends less time in the pulmonary capillary

O2 transfer then approaches diffusion limitation V. Describe the diffusion of CO2 from the blood to the alveoli

a. Gas moving from blood to alveolus must pass through: RBC membrane Plasma Capillary endothelium Interstitium Alveolar epithelium pulmonary

surfactant b. CO2 time course for CO2 transfer is similar to O2

i. Average CO2 tension in pulmonary capillary blood is 46 mm Hg, and 40 mmHg in the alveoli the CO2 diffusion gradient is only 1/10 of the O2 gradient But remember, CO2 diffuses 20 times more rapidly than O2

ii. CO2 transfer is normally perfusion-limited, although it may be diffusion limited in a person with abnormal alveolar-capillary barrier

VI. Define the diffusion capacity and discuss its measurement a. The diffusion properties of the lungs are evaluated by measuring the diffusing

capacity: (Vco = ventilation rate of carbon monoxide, PACO = arterial tension of carbon monoxide)

b. The diffusing capacity of the lungs is measured using

a single-breath technique and dilute carbon monoxide (about 0.01%)

c. Diffusing capacity (or transfer factor) rate at which O2 or CO is absorbed from the alveolar gas into the pulmonary capillaries (in mL/min) per unit of partial pressure gradient (in mm Hg)

d. Normal DLCO 30 mL/min/mm Hg e. Diffusing capacity of lungs for O2 (DLO2) 25 mL/min/mm Hg f. DLCO is decreased in diseases associated with…

i. Interstitial or alveolar fibrosis (sarcoidosis, scleroderma, and asbestosis) ii. Interstitial or alveolar pulmonary edema iii. Decrease in surface area available for diffusion (emphysema, tumors, low

cardiac output, low pulmonary capillary blood volume, decreased V/Q) Transport of Respiratory Gases in the Blood March 23, Levitzky Oxygen: Physically dissolved & combined with hemoglobin Carbon Dioxide: Physically dissolved as carbamino compounds & bicarbonate

1. Relationship between partial pressure of blood oxygen and the actual amount of oxygen dissolved in the blood

a. Partial pressure reflects the amount of oxygen physically dissolved in the blood, which is only a very small portion of the total blood oxygen content

i. 0.00003 ml O2/ torr PO2 ii. normal arterial blood (100 mm Hg) has about .3mL O2/100mL blood

b. Oxygen content also includes the amount of oxygen that binds to the Hb in erythrocytes

2. Chemical combination of oxygen with hemoglobin – and dissociation curve a. Each of four polypeptide chains bind a molecule of oxygen to the iron atom in its

heme group b. Hemoglobin rapidly, reversibly combines with oxygen (if it weren’t reversible, our

blood would have plenty of oxygen and our muscles would have none) 3. Hemoglobin saturation, oxygen-carrying capacity, oxygen content of blood

a. saturation: i. 1 gram hemoglobin carries 1.34 ml of oxygen at saturation


Page 95 of 168 ii. O2 bound to Hb = grams Hb X 1.34 X %saturation iii. % Hb saturation = O2 bound to Hb / O2 capacity of Hb X 100%

b. capacity: i. Capacity is in mL oxygen per 100 mL blood, so it depends on the Hb

capacity and also how much Hb you have ii. O2 capacity of Hb = grams of Hb x 1.34 iii. Normal = 13-15 grams of hemoglobin per 100 ml of blood iv. Average capacity = 20.1 mL (per 100 mL)

c. content: i. content = Hb-bound oxygen + dissolved oxygen

4. Physiologic consequences of the oxygen dissociation curve shape a. The oxygen dissociation curve is S-shaped, because it is steep at lower oxygen

pressures and almost flat as pressure rises above 70 mm Hg. i. the shape reflects 4 binding events, and because there is positive

cooperativity among these binding sites, the curve is not linear ii. there is also cooperativity in oxygen dissociation, facilitating efficient

oxygen delivery iii. between 10 mm and 40 mm Hg (PO2), the curve is very steep, indicating

that this is the range in which the outcome is most associated with the partial pressure

5. Physiologic factors influencing oxygen dissociation curve and their effects on oxygen transport

a. decreased PCO2, increased pH, decreased temp and decreased BPG shift curve to the left (opposites shift to right)

i. In other words, all of the signs that tell erythrocytes they are in muscle shift the curve to the right, while decreasing the oxygen affinity and allowing oxygen to be released to the muscles, and all of the signs that tell erythrocytes they are in the lungs, shift the curve to the left, increasing the oxygen affinity and pulling more oxygen onto the heme groups.

ii. All of these effects are more pronounced at lower PO2, so the role of each of these factors is probably greater in the muscle than in the lungs

iii. Temperature: oxygen is more soluble in water or plasma at lower temperatures. At 20oC, 50% more oxygen will dissolve in plasma

b. Anemia decreases peak (depressing content curve) i. anemia reduces the amount of Hb, so even at saturation, there is lowered

oxygen content in the blood c. CO decreases peak

i. Carbon monoxide is a high-affinity competitive inhibitor ii. CO also shifts the oxyhemoglobin dissociation curve to the left –

preventing unloading of oxygen iii. Normal blood levels for carboxyhemoglobin (CO bound to Hb) range from

1% in a rural non-smoker to 8% in an urban smoker. d. Nitric oxide reacts with oxyhemoglobin (oxygen bound to Hb) methemoglobin

and nitrate i. Nitric oxide can also be transported by HB S-nitrosohemoglobin or

SNO-Hb released along with O2 therefore released in low PO2 vasodilates

e. Methemoglobin i. When the iron is in the ferric state (Fe3+) it is “methemoglobin” and will

not combine with oxygen. 1. This can be caused by toxins and lack of vitamin C (I heart

nutrition tests!)


Page 96 of 168 f. Genetic variants

i. Other Hb variants exist with altered characteristics 1. Normal fetal Hb has higher affinity for oxygen (because of γ

subunits) 2. Hb Seattle and Hb Kansas have lower affinities for oxygen 3. Hb Rainier has a higher affinity for oxygen

g. Fluorocarbons can be useful as emergency transfusion sources because a lot of oxygen can just dissolve in fluorocarbon solution

h. Cyanosis occurs when more than 5g Hb/100 mL arterial blood is in the deoxy state 6. Relationship between partial pressure of carbon dioxide and the actual amount of

carbon dioxide dissolved in the blood a. Carbon dioxide is 20X more soluble in plasma than is oxygen

i. .06mL CO2/100 mL plasma at 37oC so a total of 2.4 mL in physical solution

ii. a little more than 5% of total carbon dioxide content of venous blood is in physical solution

7. Transport of carbon dioxide as carbamino compounds with blood proteins a. Carbon dioxide + terminal amine carbamino

i. can be bound to hemoglobin “carbaminohemoglobin” b. Deoxyhemoglobin supports carbamino formation – it can hold more CO2 than

oxyhemoglobin can as oxygenation occurs in the lungs, carbon dioxide is released

8. How most carbon dioxide in the blood is transported as bicarbonate a. CO2 + H20 ↔ H2CO3 ↔ H+ + HCO3- b. catalyzed by carbonic anhydrase c. Hb facilitates by accepting the liberated H+ ion improves outcome via mass

action d. bicarbonate is not a very effective buffer, but it is immediate

9. Carbon dioxide dissociation curve for whole blood a. Steeper than the oxygen dissociation curve b. Largely linear

10. Bohr and Haldane effects a. Deoxyhemoglobin is a weaker acid than oxyhemoglobin – therefore in less

oxygenated states, hydrogen ions are more readily absorbed b. Carbon dioxide can dissolve more at lower pH because its dissolution produces a

hydrogen ion: “Isohydric shift” c. Hydrogen ion association with hemoglobin lowers oxygen affinity

oxyhemoglobin dissociation curve is shifted to the right at low pH or high PCO2

(i.e., in tissue) d. Bohr effect:

i. Hydrogen ions released by dissociation of carbonic acid/formation of carbamino compounds bind to globin residues and facilitate oxygen release

e. Haldane effect: i. blood can load more carbon dioxide at the tissues, where there is more

deoxyhemolgobin, and unload more carbon dioxide in the lungs, where there is more oxyhemoglobin

Neural control of Respiration March 23, Levitzky Generation of Spontaneous Rhythmicity

1. General organization of respiratory control system


Page 97 of 168 a. Brainstem automatically generates inspiration and expiration b. Also affected by:

i. Reflexes can arise from the lungs, airways, and cardiovascular system ii. Cerebrospinal receptors iii. Cortical intervention

c. Frequency of neural discharge, the number of motor units activated, and the duration of discharge all are correlated with outcome

2. Localization of neural centers that generate spontaneous rhythmicity of breathing a. Medullary center (aka medullary respiratory center) is in the reticular formation of

the medulla, beneath the fourth ventricle b. Lesions above this level spare respiration (though pattern might be irregular), lesions

below this level do not c. Exact neuronal activity is not yet fully characterized, leading hypotheses involve

separate groups of inspiratory and expiratory neurons, which are thought to influence the muscles of inspiration and expiration, respectively, and to be mutually inhibitory

i. Dr.Levitzky seems rather unconvinced of these theories 3. Groups of neurons controlling inspiration and expiration

a. Two groups of respiratory neurons are found in the reticular formation b. Dorsal respiratory groups (DRG): are thought to be responsible for driving

diaphragmatic contraction and therefore inspiration, and is probably the initial integration site for reflexes influencing respiratory rhythm

i. located in bilateral nucelus tractus solitarius ii. project contralaterally to spine and then diaphragm iii. largely inspiratory iv. ventral efferents are many, ventral afferents are few v. largest center for CN IX and X afferents– therefore receives a lot of the

systemic information about pH, concentrations and pressures vi. I� cells increase activity when lung inflation is withheld vii. I� cells decrease activity when lung inflation is withheld viii. P cells (pump cells) are likely to be interneurons

c. Ventral respiratory groups (VRG) i. located in retrofacial nucelus, nucleus ambiguus, nucleus retroambiguus ii. inspiratory and expiratory iii. possibly pacemaking in the “pre-Bötzinger complex”

4. Other centers in brainstem that may influence spontaneous breathing rhythm a. Apneustic center: a breathing pattern of prolonged inspiration with occasional

expirations called apneusis is caused by sustained discharge of the medullary inspiratory neurons

i. likely to be site of inspiration termination b. Pontine respiratory groups

i. nuclei: 1. parabrachialis medialis 2. Kölliker-Fuse nucleus

ii. Inferior colliculus as a dividing line: 1. transection just caudal to inferior colliculus normal breathing 2. transection slightly lower, caudal to PRG apneusis

iii. Role is to fine-tune breathing pattern 1. may modulate response to hypercapnia and hypoxia

iv. pneumotaxic center: inhibits inspiration regulates inspiratory volume and respiratory rate

c. Spinal pathways


Page 98 of 168 i. All of these pathways go through the spine to get to the diaphragm, and

afferents resulting in respiratory adjustments also travel via the spine. No news here.

5. Cardiopulmonary and other reflexes influencing breathing patterns: This table is Levitsky’s 9-1 with my notes.

Stimulus Reflex Name Receptor Afferent Pathway Effects Sustained lung Inflation

Hering-Breuer inflation reflex

Stretch receptors within smooth muscle of large and small airways –“Slowly-adapting pulmonary stretch receptors”

Vagus – projects to DRG, apneustic center, PRG

Cessation of inspiratory effort, apnea, ↓ breathing frequency; bronchodilation ↑ HR, slight vasoconstrcition

Abrupt lung Deflation

Hering-Breuer deflation reflex

Juxtaopulmonary-capillary or J receptors (maybe), irritant receptors in lungs, stretch receptors in airways

Vagus Hyperpnea

Lung Inflation Paradoxical reflex of Head

Stretch receptors in lungs (precise location unknown)

Partially functional Vagus (cold)

Deep Inspiration

Negative pressure in upper airway

Pharyngeal dilator reflex

Receptors in nose, mouth, upper airways

Trigeminal, laryngeal, glossopharyngeal

Pharyngeal dilator muscle contraction

Mechanical or chemical airway irritation

Cough In upper airways, tracheobronchial tree

Vagus Cough, bronchoconstriction

Mechanical or chemical airway irritation

Sneeze In nasal mucosa - “Rapidly-adapting pulm stretch receptors”

Trigeminal, olfactory

Sneeze, bronchoconstriction, ↑BP

Facial immersion Diving reflex In nasal mucosa/face Trigeminal Apnea, ↓ HR, vasoconstriction Pulmonary embolism

J receptors in pulmonary vessels

Vagus Apnea, tachypnea

Pulmonary vascular congestion


Vagus Tachypnea, sensation of dyspnea

Chemicals Pulmonary chemoreflex


Vagus Apnea, tachypnea, bronchoconstriction

↓PaO2, ↑ PaCO2, ↓ pHa

Arterial chemoreceptor reflex

Carotid bodies, aortic bodies

Glossopharyngeal, vagus

Hyperpnea, bronchoconstriction, dilation of upper airway

↑ systemic arterial BP

Arterial baroreceptor reflex

Carotid sinus stretch receptors, aortic arch stretch receptors

Glossopharyngeal, vagus

Apnea, bronchodilation, ↓ HR, vasodilation

Muscle, tendon, joint stretch

Muscle spindles, tendon organs, proprioceptors

Spinal Feedback about work of breathing; stimulation of proprioreceptors in joints causes hyperpnea

Somatic Pain Nociceptors Spinal Hyperpnea, ↑ HR, vasoconstriction Visceral pain Apnea, ↓ ventilation

6. Temporary cortical override of breathing patterns

a. Voluntary override


Page 99 of 168 i. MVV: Maximum voluntary ventilation ii. Breathholding can temporarily override involuntary breathing iii. Useful for speech, singing, playing a wind instrument, playing dead, etc. iv. Chronic hyperventilation respiratory alkalosis

Chemical control of Ventilation March 23, Levitzky Response to Hypoxia, Hypercapnia & Hydrogen ions

1. Effects of alterations in body oxygen, carbon dioxide and hydrogen levels on breathing a. Oxygen

i. Hypoxia 1. Peripheral chemoreceptors only 2. Carotid bodies primarily 3. increased oxygen depression of central respiratory controller 4. 50-60mmHg is normal 5. High PCO2 potentiates 6. PO2 and not oxygen content is what controls this – so anemia

without acidosis does not stimulate ventilation ii. Exercise

1. increased need for oxygen can increase minute ventilation a. increases tidal volume and breathing frequency

2. up to 60% of capacity, minute ventilation increases linearly 3. above 60%, minute ventilation increases faster than oxygen

consumption, but continues to rise proportionally to increase in carbon dioxide

a. this is because of increased lactic acid H+ arterial chemoreception

4. Neural element possibly in hypothalamus b. Carbon Dioxide

i. High CO2 increases respiration 1. High = >40mm Hg 2. Linear relationship, steep slope

ii. Negative feedback system iii. Can lead to increased H levels hard to parse which drives ventilation iv. Inspired CO2 above normal levels

1. leads to dyspnea, headaches, restlessness, faintness, dulling of consciousness

2. > 15% can lead to LOC, muscular rigidity, tremors 3. >20% leads to convulsions

v. Other influences 1. sleep, narcotics, anesthesia shift curve to the right, i.e., decreases

the amount of ventilation in response to increased carbon dioxide level

a. respiratory depression is the most common cause of death in overdose of opiate alkaloids, barbiturates, anesthetics

c. Hydrogen Levels i. Between 20nEq/L and 60nEq/L, there is a linear relationship between

[H+] and ventilation ii. Metabolic acidosis:

1. Acidotic stimulation of the peripheral chemoreceptors increased alveolar ventilation arterial CO2 falls CSF CO2 falls (CSF and blood are in dynamic equilibirum) pH of CSF increases


Page 100 of 168 decreased stimulation of central chemoreceptor breathing is normalized

2. This is counterintuitive because hyperventilation would help reduce acidosis – now, instead, metabolic factors will have to increase pH

3. Central chemoreceptor responds more to CO2 in the CSF than to pH in the blood, which is why this overly complicated mechanism is the one driving ventilation

2. Sensors of respiratory system for oxygen, carbon dioxide and hydrogen levels a. Peripheral chemoreception

i. control 10-20% of the steady state respiration 1. up to 1/3 of control when arterial carbon dioxide levels are rapidly

shifting ii. arterial chemoreceptors – in carotid and aortic bodies

1. exposed to blood iii. Increase firing rate in response to

1. Increased PCO2 2. Decreased PO2 3. Decreased pH

iv. System is rapid and sensitive – i.e., the speed and air amount of one breath v. Carotid bodies effect breathing more than aortic bodies do vi. Some drugs act on these sensors

1. cyanide, dinitrophenol stimulate carotid body hypoxia b. Central chemoreception

i. control 80-90% of the steady state respiration ii. located bilaterally near the ventrolateral surface of the medulla

1. exposed to CSF 2. On brain side of blood-brain barrier

a. CO2 can diffuse, but bicarb can’t b. Carbon dioxide is normally at 50mmHg in the brain

3. Do not respond to hypoxia – only carbon dioxide and H Acid-Base Balance 3/24/06, Levitzky

1. Define acids, bases, and buffers. a. Acids can donate hydrogen ions

i. Strong acids almost completely dissociate in water b. Bases can accept hydrogen ions c. Buffer- a mixture of substances in solution that resists changes in hydrogen ion

concentration when acids or bases are added i. Buffers are usually composed of a weak acid and its conjugate base

2. List the buffer systems available in the human body. a. Buffering ability is measured as buffer value

i. Amount of hydrogen ions (mEq/L) that can be added to or removed from a solution with a resultant change of one pH unit

b. Bicarbonate Buffer System- the major buffer system in our bodies i. CO2 + H2O↔ H2CO3↔H+ + HCO3-

ii. carbonic anhydrase is catalyst c. Phosphate Buffer System

i. H2PO4-↔ H+ + HPO42- d. Proteins

i. Plasma proteins, specifically hemoglobin


Page 101 of 168 1. the imidazole group of histidine has buffering capacity, and there

are many histidines in hemoglobin 3. Describe the interrelationships of the pH, the PCO2 of the blood, and the plasma

bicarb concentration and understand the modified Henderson equation. a. Henderson-Hasselbalch equation

i. pH= pK + log [A-]/[HA] ii. This equation can be modified for the bicarbonate buffering system

1. pH=pK’ + log [HCO3-]p/[0.03xPCO2] a. pK’ here is the pK for bicarb

2. [HCO3-]p is the plasma concentration of bicarb, which is the base in the dissociation equation (see 2.b.i.)

3. Carbon dioxide and carbonic acid are the undissociated acids, (concentration of carbonic acid is negligible).

4. 0.03 mmol of CO2 per mmHg will dissolve in a liter of plasma b. The relationship between pH, the PCO2 of the blood, and the plasma bicarb can be

expressed in the pH-bicarbonate diagram (Figure 8-1) i. Bicarb is the y-axis, pH is the x-axis ii. ↑ pH ↓ [HCO3-]p iii. Curve gets shifted to the right with increasing PCO2

4. State the normal ranges of arterial pH, PCO2 and bicarb concentration and define alkalosis and acidosis.

a. Plasma bicarb: 24 mmol/L (normal range 23-28mmol/L) b. Arterial PCO2: 40 mmHg (normal range 35-45 mmHg) c. pH: 7.40 (normal range 7.35-7.45) d. Acidosis

i. Respiratory: ↑arterial PCO2 ↓ arterial pH ii. Metabolic: Arterial PCO2 remains constant but ↓ arterial pH

e. Alkalosis i. Respiratory: ↓arterial PCO2 ↑ arterial pH

ii. Metabolic: Arterial PCO2 remains constant but ↑ arterial pH 5. List the potential causes of respiratory acidosis and alkalosis and metabolic acidosis

and alkalosis. a. Respiratory acidosis

i. Depression of respiration ii. Neuromuscular disorders

iii. Chest wall restriction iv. Lung restriction v. Pulmonary parenchymal diseases

vi. Airway obstruction b. Respiratory alkalosis

i. CNS problems (ex: anxiety, tumors) ii. Drugs or hormones

iii. Bacteremias iv. Pulmonary disease v. Overventilation with mechanical ventilator

vi. Hypoxia- high altitude c. Metabolic acidosis

i. Ingested drugs or toxins ii. Loss of bicarb (ex: diarrhea, pancreatic fistulas, renal dysfunction)

iii. Lactic acidosis iv. Ketoacidosis (ex: diabetes) v. Inability to excrete hydrogen ions


Page 102 of 168 d. Metabolic alkalosis

i. Loss of hydrogen ions (ex: vomiting, gastric fistulas) ii. Ingestion or administration of excess bicarb or base (ex: antacids)

6. Discuss the respiratory and renal mechanisms that help to compensate for acidosis and alkalosis.

a. Respiratory compensation i. Metabolic acidosis

1. ↑ [H+] activate chemoreceptors ↑ alveolar ventilation ↓ arterial PCO2

ii. Metabolic alkalosis 1. ↓ alveolar ventilation ↑ arterial PCO2

b. Renal compensation i. Respiratory acidosis and Metabolic acidosis of non-renal origin

1. ↑ secretion H+ ions into the tubular fluid ii. Respiratory alkalosis and Metabolic alkalosis or non-renal origin

1. ↓secretion H+ ions and ↓ bicarb reabsorption iii. Renal compensation operates more slowly than respiratory. Respiratory is

instantaneous and renal can take 3 to 6 days. 7. Evaluate blood gas data to determine a subject’s acid-base status.

a. The best way to do this is by doing the examples in the book. Here are some useful terms defined:

b. Base excess (deficit)- # mEq acid/base needed to titrate 1L of blood to pH 7.4 at 37ºC if Pa CO2 were held constant at 40 mmHg

i. Base excess ranges from -2 to +2 c. Anion gap= [Na+]-([Cl-] + [HCO3-])

i. Normal range is 12±4 mEq/L ii. Can help determine the cause of metabolic acidosis if anion gap is great,

acidosis caused by lactic acidosis or ketoacidosis. The Respiratory System Under Stress: Exercise; Hypobaric and Hyperbaric Environments 3/24/06 Levitzky

1. Identify the physiological stresses involved in exercise. a. Respiratory stress

i. ↑ oxygen consumption ii. ↑ carbon dioxide production

b. ↑ lactic acid production c. ↑ metabolic needs of muscles and other peripheral tissues

2. Predict the responses of the respiratory system to acute exercise. a. The data below reflect experiments done on people exercising in the verticle positon

only. Experiments evaluating horizontal exercise can be performed for 1 point for foundations in medicine.

b. ↑VT (↑ RV, FRC, ↓IRV, TLC, & ERV and Vc remain constant) ↑ work to overcome elastic recoil of lungs and chest wall (which are greater at higher lung volumes)

c. ↑ airway resistance because greater rates of airflow d. ↑ venous return ↑ central blood volume slight ↓ TLC e. ↑ breathing frequency f. slight ↑ anatomic dead space due to airway distention; ↓ alveolar dead space

physiological dead space remains constant i. Since VT increases, ratio of physiological dead space to tidal volume

(VD/VT) decreases


Page 103 of 168 g. ↓ PVR due to recruitment and distention (overcoming effects of extravascular

compression from ↑VT) h. V/Q relationship improved (V/Q ratio increases, representing an optimal

relationship) throughout anatomical regions of the lung (now the entire lung is getting matched, i.e., ratio of 1, or better) because ventilation increases more than perfusion

i. V/Q will be in the range of 2.0 to 4.0 for the entire lung i. ↑ diffusing capacity of lung

i. ↑ pulmonary blood flow ii. recruitment of capillaries ↑ SA for gas exchange

iii. ↑↑↑ blood flow velocity ↑ possibility of diffusion limited gas transfer iv. ↑PO2 and ↓ PCO2 greater partial pressure gradients for gas diffusion

j. ↑ oxygen unloading i. oxyhemoglobin dissociation curve shifted to right because ↑ PCO2, H+, and

temperature ii. ↓ PO2 in exercising muscles

k. if exercise is severe enough to cause metabolic acidosis (from lactic acidosis) stimulate chemoreceptors for ventilatory compensation

3. Describe the effects of long-term exercise programs (training) on the respiratory system.

a. Max and resting ventilation remain the same b. ↓ Ventilation at submaximal loads c. ↑ Strength and endurance of respiratory muscles d. ↑ Pulmonary diffusing capacity b/c of ↑ blood volume and CO

4. Identify the physiological stresses involved in the ascent to altitude. a. ↓ Total barometric pressure, but not a constant decrease with ascent

i. Decreases pressure gradient b. Reduced oxygen available

5. Predict the initial responses of the respiratory system to high altitude. a. ↓ alveolar and arterial PO2 stimulate arterial chemoreceptors ↑ alveolar

ventilation ↓alveolar and arterial PCO2 respiratory alkalosis “diffusion” of CO2 out of CSF ↑pH of CSF

b. ↑ rate and depth of breathing ↑ work of breathing i. ↑ breathing rate hypocapnia and respiratory alkalosis

ii. Oxygen is still too low because there isn’t much available, but carbon dioxide is also too low, leading to alkalosis even in hypoxia

c. greater transpulmonary pressure needed to generate greater VT ; need to overcome vascular engorgement and ↑ interstitial fluid volume of lung ↓ VC

d. ↑ ventilatory rate ↑ active expiration dynamic compression of airways ↑ resistance work of breathing

e. ↑ airflow rate b/c of ↓ gas density f. ↓(VD/VT) with greater VT g. more uniform regional distribution of alveolar ventilation

i. previously collapsed alveoli will be ventilated h. ↑ arterial chemoreceptor stimulation and lung inflation symp stimulation ↑ CO,

HR, and systemic BP i. hypoxic pulmonary vasoconstriction + ↑CO + ↑ symp stimulation of large

pulmonary vessels ↑MPAP, recruiting capillaries and abolishing Zone 1 j. PO2 decreases more in alveoli than in mixed venous blood ↓ partial pressure

gradient for oxygen; partially offset by ↑ CO and pulmonary artery pressure


Page 104 of 168 k. ↑ Hb concentration due to fluid shifting to extravascular space, not increased

erythrocyte production l. two possibilities of effect of cerebral circulation

i. first thought altitude caused cerebral hypoperfusion: hypocapnia cerebral vasoconstriction ↓ blood flow (and a lower oxygen content) and alkalosis of CSF

ii. now think cerebral hyperperfusion and edema: hypoxia cerebral vasodilation ↑hydrostatic pressure on cerebral capillaries edema ↑ ICP distort intracranial structures

6. Describe the acclimatization of the cardiovascular and respiratory systems to long-term exposure to altitude.

a. Renal compensation- within 1 day i. ↑ base excretion; H+ conserved

b. Erythropoiesis- within 3 to 5 days i. ↑ blood viscosity and ventricular work

ii. ↑ 2, 3 BPG to release oxygen to tissues c. hypoxic stimulation of arterial chemoreceptors persists d. Ventilatory response curve to CO2 shifts to the left

i. For any given alveolar or arterial PCO2, the ventilatory response is greater after several days at high altitude

ii. Occurs simultaneously with CSF return to normal pH and relief of cerebral edema and ↑ICP

1. due to ↑ reabsorption of CSF, autoregulation of cerebral blood flow, sympathetic-mediated vasoconstriction

e. CO, HR and BP return to normal within a few days i. ↓ symp activity or change in symp receptors

ii. HPV and pulmonary hypertension persist RV hypertrophy RV failure secondary to pulmonary hypertension (known as cor pulmonale)

See Table 11-2 for chart describing physiological responses and timeline after ascent to high altitude. GI Epithelial Barrier Function: Esophageal, Gastric, and Duodenal Mucosa Dr. Orlando 4/3/2006

I. Pre-epithelial, epithelial, and post-epithelial defense against acid injury for the esophageal, gastric and duodenal mucosae A. Pre-epithelial defenses - on the luminal side of the epithelium.

1. Mucus 1. Thick, viscoelastic layer that provides lubrication against

mechanical injury 2. Secreted via exocytosis from gastric glands in isthmic and foveolar

regions 2. Unstirred water layer

1. There is a layer of water that is stagnant near the epithelium 2. Provides an additional barrier of defense and a place for the

bicarbonate to reside (for maximum effectiveness) 3. Bicarbonate buffer

1. ⇑ [HCO3-] in unstirred water layer; buffers against H+ 2. Carbonic anhydrase H+ and HCO3-

a. H is the stomach acids


Page 105 of 168 b. HCO3 buffers

3. Alkaline tide – when parietal cell takes carbonic acid and it dissociates into H+, and HCO3 H+ is secreted into lumen HCO3 exits basolateral membrane via Cl/HCO3 exchanger enters blood HCO3 taken to buffer downstream surface cells

a. Only in stomach B. Epithelial defense – components of epithelium itself

1. Structural 1. Phospholipid bilayer

a. Reflects ions with hydrophobic core b. Reflects larger particles except at channels/pores c. Selective entrance into cell

2. Apical junctional complex (AJC) = tight junctional complex a. Zonula occludens = tight junction circumferential

component that restricts paracellular diffusion and maintains cell surface domains

b. Zonula adherens = adhesion belt circumferential, transmembrane linking proteins cell-cell adhesion

c. Desmosomes = macula adherens spot-welds reinforced cell-cell adhesion

2. Functional 1. Cellular bicarb – buffers acid entering epithelial cells when

buffering capacity is exceeded cell becomes acidic and pumps protons out of basolateral membrane

C. Post-Epithelial defense – intercellular space’s defense 1. Bicarbonate in blood

1. Neutralizes acid that leaks through 2. H+ can leak b/t cells tricks body to thinking blood is acidic

wants to equalize pH neutralized by cellular HCO3- and exports H+ via H/Na exchanger

2. Esophageal intercellular glycoproteins 1. “peanut-butter” material that fills intercellular space ⇑ stickiness

to ⇓ H+ that can get through II. Discuss the major differences between the above defenses for the esophagus,

stomach and duodenum A. Esophagus

1. No mucus secretion here 2. Lined with stratified squamous epithelium

1. Relied on heavily against mechanical abrasions 3. Has the intercellular glycoproteins (peanut butter) allows for a better

post-epithelial defense b/c of limitations of stratified squamous epithelium

B. Stomach 1. Lined with simple cuboidal epithelium 2. Has no intercellular glycoproteins has better tight junctions 3. Has mucus and unstirred water with bicarbonate 4. Alkaline tide

C. Duodenum 1. Mucus 2. Simple cuboidal epithelium 3. No intercellular glycoproteins


Page 106 of 168 4. No alkaline tide 5. Dilutes ⇑ [H+] with water 6. Lots of reflexes to slow stomach if too acidic (see later lectures)

III. Describe the two mechanisms by which the esophagus, stomach, and duodenum repair their epithelial lining following acid injury A. Regeneration/Replication

1. Synthesis of new cells – takes time B. Restitution

1. When cells migrate to fill a hole – faster but only works superficially 2. 30-60 minutes

C. Mechanism: Ulcer from NSAIDs/ASA/H. Pylori no Δ in amount of H+, the Δ is in the defense mechanism in stomach and duodenum irritant prostaglandin/COX release ⇑ mucus secretion, HCO3 secretion, and ⇑ blood flow.

GI Motility I: Esophagus and Stomach Regulation of Swallowing and Gastric Emptying Orlando April 4, 2006

1. List the neuroanatomic components involved in the act of swallowing a. Upper 1/3 of esophagus is striated muscle and lower 2/3 is smooth muscle b. Musculature of esophagus is divided into inner circular and outer longitudinal layers c. Each end of the esophagus is closed off by sphincters

i. UES, upper esophageal sphincter, striated prevents inspired air from entering esophagus (anatomically the cricopharyngeus muscle)

ii. LES, lower esophageal sphincter, smooth prevents reflux of gastric contents into the esophagus

d. Motor Innervation of esophagus Vagus nerve innervates the entire esophagus e. Sensory innervation of esophagus submucosal (Meissner’s) plexus located

between the muscularis mucosae and circular muscle layers 2. Discuss the oral/pharyngeal and esophageal phases of swallowing

a. Oral (voluntary) phase the tongue forms a bolus pushes up and back against hard palate bolus forced into oropharynx

b. Pharyngeal phase (involuntary) coordinated by the swallowing center in the medulla and lower pons (mediated by ACh via CN V, IX, and X)

i. initiated by oropharyngeal sensory fibers that detect food ii. Nasopharynx is closed by the soft palate, preventing regurgitation of food

into the nasal cavities iii. Palatopharyngeal folds are pulled medially forms a passageway iv. Glottis and vocal cords are closed, epiglottis swings down over the larynx

food goes toward the esophagus and away from the airways v. The bolus of food is pushed into the esophagus by the peristaltic

contractions of the pharynx and the opening of the UES vi. Respiration is inhibited for the duration of swallowing (1-2 seconds)

c. Esophageal (involuntary) phase food is propelled into the stomach, strength of peristaltic contractions is proportional to the size of the bolus

i. UES contracts to prevent regurgitation, LES relaxes to facilitate passage ii. Peristaltic wave travels slowly (3-4 cm/sec) taking about 8 seconds to push

food from mouth to stomach


Page 107 of 168 iii. As food enters stomach, LES contracts to prevent regurgitation of food

into esophagus 3. Define the differences between vagal innervation of esophageal skeletal and smooth

muscle a. Cholinergic fibers that innervate the striated muscle (Upper 1/3 and UES) arise

from the Nucleus Ambiguus and directly synapse on muscle motor end plates b. Pre-ganglionic cholinergic fibers that innervate the smooth muscle (Lower 2/3 and

LES) arise from the Dorsal Motor Nucleus of X and synapse on neurons in the myenteric (Auerbach’s) plexus (located between circular and longitudinal muscle)

c. Post-ganglionic cholinergic fibers that innervate smooth muscle synapse on motor end plates for contraction of longitudinal and circular smooth muscle

d. Post-ganglionic non-adrenergic, non-cholinergic (NANC), possibly Vasoactive intestinal peptide (VIP), are inhibitory fibers that cause LES relaxation NO is the final mediator of LES relaxation

4. Discuss the physiologic role of the UES and LES and esophageal peristalsis in digestion and (whole organism) protection

a. UES striated; contracts to prevent respired air from entering esophagus and relaxes to allow ingested material to enter esophagus

b. LES smooth; contracts to prevent gastric regurgitation into esophagus and relaxes to allow ingested material into the stomach

c. Esophageal peristalsis (primary and secondary) function to keep ingested material moving toward the stomach

5. Describe the differences between primary and secondary peristalsis in the esophagus a. Primary esophageal peristalsis is initiated by swallowing

i. Coordinated by the sequential activation of motor units in a craniocaudad sequence by cholinergic excitatory stimuli received from the Vagus nerve

ii. Vagotomy would prevent the initiation of primary esophageal peristalsis b. Secondary esophageal peristalsis is initiated by the presence of food within the

esophagus; any material remaining in the esophagus stimulate mechanical or irritant receptors

i. Coordinated by the intrinsic nervous system of the esophagus (myenteric plexus)

ii. Stretch Afferents intrinsic nervous system 1. Because intrinsic rather than vagal nerves are involved, vagotomy

would have little or no effect on secondary esophageal peristalsis 6. Define the mechanism responsible for transient LES relaxations (TLESRs) and the

importance of these phenomena in health and disease a. TLESRs spontaneously occurring reflex characterized by LES relaxation in the

absence of swallowing or overt esophageal distension b. Mediated by vagal activation of NANC inhibitory stimuli to the LES c. TLESRs are associated with almost all reflux events in healthy subjects and a

primary cause of reflux events in those with reflux esophagitis i. “Belch” reflex air is swallowed during eating and produces fundic

distension which results in coordinated relaxation of both UES and LES 1. Gaseous distension of fundus produces a TLESR air enters and

distends long segment of esophagus 2. Distension of esophagus induces a reflex relaxation of the UES

7. List the anatomical compartments of the stomach and explain how each contributes to the processing of a meal

a. The 3 functional parts of the stomach are the fundus, corpus (body), antrum


Page 108 of 168 b. The 3 major functions of gastric motility are storage, mixing/grinding/digestion,

and emptying c. Storage when food enters the stomach, the orad region, primarily the fundus,

enlarges to accommodate food d. Mixing/Grinding/Digestion The presence of food in caudad stomach, primarily

the corpus and antrum, increases the contractile activity of the stomach i. The enhanced contractile activity (a combination of peristalsis and

retropulsion) mixes the food with stomach acid and enzymes, breaking it into smaller and smaller pieces

ii. Mushed up, food is “Chyme” e. Emptying When the chyme is broken down into small enough particles, it is

propelled through the pyloric sphincter into the intestine 8. Define the terms basic electrical rhythm (BER), cells of Cajal, and action potentials.

Explain the role of each in producing peristaltic gastric contractions a. Peristaltic contraction are initiated near the fundal-corpus border and proceed

caudally, producing a peristaltic wave that propels food toward the pylorus i. At pylorus, a mass contraction of the terminal antrum pushes the food back

toward the corpus through a narrow antral ring retropulsion ii. <2mm pieces can get through

b. Peristaltic contractions produced by periodic change in membrane potential, called slow waves, or the basic electrical rhythm these waves are responsible for the rhythm and force of gastric contractions

c. Gastric slow waves are initiated by pacemaker cells within the wall of the stomach, the cells of Cajal, which have automaticity and depolarize spontaneously

d. Slow waves consist of an upstroke and plateau phase and occur at a rate of approximately 3-4 waves/min

e. Velocity of waves is 1cm/sec when they sweep over the corpus and increases to 3-4cm/sec in the antrum

f. Force of peristalsis force of contractions regulated by gastrin and ACh i. ACh released by vagus nerve in response to gastric distension ii. Gastrin released from G cells in antrum in response to rising antral pH and

presence of peptides from protein digestion iii. These hormones increase the size of the slow wave plateau potential, which

increases the amount of Ca2+ entering the cell from the extracellular fluid 1. Increased contractile activity due to increased amplitude and

duration of the plateau phase of the slow wave 9. Discuss the mechanism responsible for being able to eat a complete meal before

feeling full a. As food enters stomach, contractile activity of the fundus is inhibited, enabling the

stomach to store 1 to 2 L of food b. Accommodation is initiated in response to a bolus of food entering stomach.

Stretch receptors in orad stomach detect presence of food and initiate a vagovagal reflex producing receptive relaxation

c. Receptive relaxation is the process by which the fundus accommodates the meal without increasing gastric pressure

d. The inhibitory neurotransmitter responsible for receptive relaxation is either VIP or NO

e. Vagotomy prevents or greatly diminishes receptive relaxation because vagal reflexes produce both processes

GI Motility II: Small and Large Bowel April 5, Orlando


Page 109 of 168 Food Processing, Bowel Sterility and Storage, and the Act of Defecation

1. 3 ways the duodenum regulates gastric emptying Chyme is sampled by the dudodenum and looks at acidity, tonicity and fattiness, which determines what is released. a. acidity secretin release

i. released from S cells of the duodenum ii. reduces gastric contractions iii. stimulates bicarb secretion

1. neutralizes acid b. fat cholecystokinin release

i. reduces gastric contractions 1. reduces peristalsis less fat coming into duodenum

ii. stimulates bile secretion 1. fat absorption

c. hypertonicity vagal innervation i. reflex reduces gastric contractions ii. stimulates salt and water secretion

1. dilution 2. 2 important functions of migrating motor complex:

a. The Migrating Motor Complex or the MMC has 3 phases: i. phase I – intestine is quiescent ii. phase II- sporadic contractions iii. phase III – regular peristaltic contractions originating in gastric antrum

b. MMC takes 2 hours to cycle, and ceases if oral ingestion occurs i. the peristaltic wave occurs every 60-90 minutes during the interdigestive

period, (aka fasting state) ii. One bolus can take 3-4 hours to travel the entire small intestine

c. 2 Functions: i. Removes undigested material from the stomach

1. including items larger than 2 mm which therefore could not be part of normal digestion, such as condoms with heroin

ii. Sweeps residual chyme from the small intestine into the cecum – keeps bacterial colonization in the small intestine to a minimum

1. In scleroderma, for example, MMC is absent and bacteria overgrow the small intestine, interfering with digestion and absorption of nutrients

a. treat with antibiotics, somewhat effective 3. 3 major differences between fed and fasting states

Fed State Fasting State = at least 2 hours since last meal

Duodenal action MMC: from the antrum of the stomach to the end of the ileum. Stops immediately when oral ingestion begins. More info above in 2C.

Gastroileal reflex / Gastrocolic reflex: The stomach sends neurohumoral signals to the ileum and colon to create a mass movement because the stomach responds to its being filled, so there needs to be room made. The gastroileal reflex is mediated by extrinsic ANS and maybe gastrin. The gastrocolic reflex is

MMC in the stomach is initiated by vagal impulses that release motilin


Page 110 of 168 mediated by the parasympathetic system, CCK and gastrin. Secretin stimulating bicarb secretion from pancreas for acid neutralization CCK stimulating bile secretion for fat absorption Vagus stimulates salt and water secretion for dilution of luminal content

Motilin, secreted by enterochromaffin cells of the small intestine, is important in initiating MMC in the duodenum and small intestine, which does not depend on extrinsic nerves

4. Difference between small intestinal segmentation and peristaltic waves

a. segmentation waves i. mix intestinal contents ii. break food into smaller pieces that get pushed away from the point of

contraction (one bit oral, one bit caudal) iii. no net movement of chyme

b. peristaltic waves i. propel food caudally ii. Smooth, progressive, coordinated iii. still in short segments iv. basic electrical rhythm

1. 12/minute in duodenum 2. 10/minute in jejunum 3. 8/minute in ileum

5. Anatomical parts of the colon and their functions in processing luminal contents a. Cecum

i. ileocecal valve – smooth muscle ii. remove ions in water

b. Ascending colon i. remove ions in water

c. Transverse colon i. storage

d. sigmoid colon i. storage

e. rectum i. waste elimination ii. internal anal sphincter – smooth muscle iii. External anal sphincter, puborectalis muscle – skeletal muscle

6. “Call to stool” after eating a. Gastrocolic reflex: a meal enters your stomach contents of colon move into

rectum b. Rectum fills with material rectosphincteric reflex: internal anal sphincter relaxes c. at 25% capacity, there is the urge to defecate, which is prevented by voluntary

contraction of the external anal sphincter 7. Role of haustrations and mass movements in colon function

a. haustrations –remember haustra are the compartments created by the contraction of circular muscle – bring material into contact with the epithelium

i. this is the same thing as segmentation waves b. mass movements – occur over long segments of colon – are peristaltic and occur 1-

3 times a day i. move luminal content from right to left colon increasingly dehydrated ii. over 2-3 days material reaches rectum


Page 111 of 168 8. Defecation reflex and the role of sphincters and puborectalis muscle in maintaining

continence a. mass movement moves solid material into rectum b. rectum is distended c. reflex relaxation of internal anal sphincter

i. NO ii. vasoactive intestinal peptide (VIP)

d. luminal content moves to anal canal e. sensory receptors matter state of waste is determined

i. anal canal samples f. External anal sphincter – mediated by acetylcholine

i. relax to allow passage of waste (cholinergic output inhibited) 1. levator ani, puborectalis (reins in anal canal), and external anal

sphincter relax 2. pelvic floor relaxation, along with squatting position, straightens

the anorectal angle facilitating evacuation ii. contract to prohibit passage of waste (cholinergic output stimulated)

1. rectum undergoes receptive relaxation to accommodate 2. internal anal sphincter relaxes 3. external anal sphincter and levator ani are under voluntary control

a. contraction prevents evacuation 4. rectum exhibits receptive relaxation – just like the fundus of the

stomach – and then the internal sphincter stops sensing stretch, so it contracts, returning matter upwards

5. rectosigmoid stores waste 6. other mammals can also put off defecation

GI secretion I: Mouth and salivary glands The role of secretions in digestion and protection 4/6/06 Dr. Orlando, Handout by Dr. Edd Rabon

1. Discuss the structure and function of the salivary glands a. 3 major pairs of salivary glands

i. Submandibular- mixed seromucinous-secreting ii. Sublingual- mixed seromucinous-secreting iii. Parotid- primarily serous-secreting

1. all water all the time b. Glands composed of units called salivons

i. Each salivon composed of an acinus, an intercalated duct, and a striated collecting duct

ii. Ducts are lined by simple columnar epithelium c. Acinus surrounded by myoepithelial cells on serosal side

i. Can contract to enhance rate of salivary secretion d. Salivon has both sympathetic and parasympathetic efferent innervation

i. Symp- T1-T2 of spinal cord ii. PSymp- superior and inferior salivary nuclei, transmitted by CN VII and IX

2. Describe how saliva is produced and its flow regulated a. Saliva production begins in acinus as ultrafiltrate of blood

i. Serous salivary acinar cells transport ultrafiltrate of blood into lumen of acinus (see Fig 32-6 in the physio handout for images)

1. Basolateral membrane: a. Na/K ATPase b. Na/K/2Cl cotransporter


Page 112 of 168 2. Apical membrane:

a. K channel b. Cl, HCO3- “co-channel” c. Na enters lumen partly via tight junctions between

epithelial cells b. Ultrafiltrate enters ducts where it is modified by absorption and secretion

i. Striated and excretory secrete K+ and HCO3- and reabsorb Na+ and Cl- via a series of ion exchangers and channels, driven by a basolateral Na/K pump (see Fig 32-5 in the physio handout for images)

1. Apical membrane: a. Na channel into the cell b. Cl/HCO3- exchanger, pumps HCO3- into duct lumen c. Na/H exchanger, pumps Na into cell d. H/K exchanger, pumps K into duct lumen

2. Basolateral membrane: a. Na/K ATPase, pumps Na out of cell, K in b. K channel, releases K into blood c. Cl channel, releases Cl into blood d. H/Na exchanger, pumps H into blood, Na into cell

c. Final product is hypoosmolar and rich in K+ and HCO3- in comparison to blood i. Basal rate of saliva flow 0.5 ml/min, can be stimulated up to 4 ml/min ii. During a meal salivary flow rates increase, so saliva has less time to be

modified by absorption and secretion saliva is less hypoosmolar and lower in K+ and HCO3-

d. Completely under neural control (not hormonal like other GI systems) e. Simultaneously innervated by sympathetic and parasympathetic

i. It’s the only thing we’ve seen that uses both arms of the autonomic nervous system, and it makes sense – you always need to lube when things will be in your mouth, whether it’s food (parasympathetic) or people (sympathetic)

ii. Norepi (acting on α and β adrenergic receptors), Ach, and substance P ↑Ca2+ intracellulary ↑ amylase secretion and fluid secretion

iii. Norepi also ↑ cAMP levels ↑ amylase secretion f. Effects of sympathetic and parasympathetic stimulation on salivary secretion

i. Sympathetic 1. scant salivary output 2. transient duration of flow 3. protein-rich 4. cAMP is cytosolic messenger 5. if denervated, glands will not atrophy 6. Note: cotton mouth occurs during sympathetic stimulation because

of #s 1, 2 and 3, especially 3 ii. Parasympathetic

1. copious salivary output 2. sustained duration of flow 3. protein-poor, watery (no cotton-mouth) 4. Ca2+ is cytosolic messenger 5. if denervated, glands will atrophy, so psymp involved in gland

growth, not just salivation 3. List 5 major components in saliva and identify their contribution to digestive or

protective function of the individual a. Water

i. Digestive function


Page 113 of 168 1. lubrication of bolus for mastication and swallowing

ii. Protective function 1. dilute potentially noxious components of food (makes bolus less

osmotic protective because it brings hyperosmotic foods closer to isoosmotic)

2. bolus temperature control 3. oral hygiene

b. Mucus i. Digestive function

1. lubrication of bolus for mastication and swallowing ii. Protective function

1. lubrication of bolus against mechanical trauma c. Alpha amylase

i. Digestive function 1. starch digestion

ii. Probably vistigial; not necessary d. Lingual lipase

i. Digestive function 1. fat digestion

ii. Probably vistigial; not necessary e. HCO3-

i. Protective function 1. neutralize acid in food 2. neutralize HCl reflux from stomach 3. antibacterial by neutralization

f. Other components i. Lactoferrin- antibacterial by binding iron ii. Muramidase- antibacterial by hydrolyzing cell walls iii. Epidermal Growth Factor (EGF)- cell growth and repair iv. R protein – binds B12 temporarily before intrinsic factor binds

Gastric Secretions II – Stomach Dr. Lenard Lichtenberger 4/7/2006

I. Endocrine Regulation of Gastrointestinal Function A. Mostly in the antrum of the stomach B. Gastrin – made by G cells in antrum; granules are dumped into blood

1. Released with presence of proteins in stomach/mouth (sham) 2. Stimulates the release of H+ into lumen (80% of acid output) 3. Stimulates GI mucosal proliferation (GI trophic hormone) in the body of

the stomach 4. Stimulates pancreatic enzyme secretion (CCK) 5. Stimulates contractile activity of GI smooth mm – promotes gastric

motility C. Secretin – released by duodenal cells when there is acid in the duodenum; secretin

inhibits gastrin-stimulated parietal cell activity D. CCK – released by I cells of duodenum in presence of food (protein and fat)

1. initiates gallbladder contraction E. GIP – released by K cells in the small bowel in response to fat , inhibits parietal cell

function (HCl secretion) F. Neurotensin – released by terminal ileum, in response to fat inhibits gastrin food-

stimulated acid secretion


Page 114 of 168 G. Peptide YY (PYY) – released from intestine from fatty meal, inhibits feeding and

vagal stimulated gastric acid secretion II. List the overall physiological functions of the GI system

A. Food 1. Digestion 2. lubrication 3. absorption of food

B. Acid barrier against bacterial infection III. List the major functions of the GI system that are regulated by GI hormones –

see LO I IV. Describe and contrast the three forms of regulation; provide examples of each

A. Endocrine – see LO I/III B. Paracrine –

1. Histamine 1. ECL cells store histamine paracrine regulator of parietal cell 2. ECL cells stimulated by ACh and gastrin to release histamine 3. Histamine binds and activates parietal cells via H2 receptors 4. cAMP is second messenger increased H+ secretion

2. Somatostatin – released by D cells; release is initiated by stomach acid, inhibits parietal cell directly and indirectly (opposes gastrin cells)

C. Neurocrine – ACh 1. Binds M3 receptor on parietal cell to release intracellular Ca2+ 2. Indirectly stimulates acid output activates G cells release of Gastrin

releasing peptide (GRP) and inhibiton of somatostatin release V. Gastric secretion

A. Histamine plays a major role opens Cl- channels B. Proton pumps as α (catalytic) and β (localization/membrane) subunits

1. Can be blocked with drugs C. Parietal cells

1. Mitochrondria pump H+ against gradient 2. Canaliculi fuse w/ tubular vesicles ⇑ surface area and exposes

proton pumps and K+ channels D. Gastric secretion is isotonic to the blood at all secretory rates

VI. List the major physiological functions of the stomach – See LO II VII. Describe/diagram an acid secreting (parietal) cell in the resting and stimulated

state Refer to figures 3, 4 and 5 in the lecture notes. A. Stimulated state: Morphological changes occur that allow parietal cells to secrete

HCl. 1. secretory canaliculi are formed from tubulovesicles (which have

membranous H+/K+ ATPase exchangers) fusing with parietal cell membranes. H+ is secreted via exchanger pump, Cl- is secreted via membranous Cl- channels.

2. Gastrin and ACh act via calcium messenger to cause morphological change, while histamine acts via cAMP messenger

3. Resting state: Tubulovesicles are sequestered into the cell, away from the cell membrane, so H/K exchanger can no longer actively secrete H+ into lumen, and HCl secretion ceases.

1. High H+ (low pH) release of somatostatin & secretin inhibition of parietal cells (somatostatin directly & indirectly,


Page 115 of 168 secretin indirectly only – indirect mechanisms are via gastrin inhibition)

VIII. Describe the biochemical steps involved in gastric acid secretion A. H+ and Bicarb are produced in parietal cells via carbonic anhydrase conversion of

water and carbon dioxide B. Bicarb and Chloride are exhcanged on basolateral membrane; Chloride into cell,

Bicarb into blood (=alkaline tide) C. Cytosolic Cl and K diffuse down leak channels in canaliculi to enter the lumen D. H+ ions are pumped against their concentration gradient into the lumen via

H+/K+ ATPase IX. Describe the anatomical changes that occur when a parietal cell goes from the

resting to the stimulated state see LO VII X. Describe how proton pump inhibitors such as omeprazole interact with the H/K

ATPase to inhibit gastric acid secretion A. Accumulates at pH = 3.0 B. In activated form, makes a disulfide bridge with the parietal cells H/K ATPase

irreversible inhibition b/c can’t pump H+ into lumen any more C. Takes a few days because it can only inhibit pumps in active cells cumulative

effect to alkalinize stomach XI. Describe the fluxes of Na, Cl, and H in the parietal cell during acid secretion

A. Na/H exchange (uses Na gradient from Na/K ATPase) pumps H+ out 1. on basolateral membrane\

1. Dr.Lichtenberger’s Notes mention this but do not explain the significance

B. H/K ATPase pumps H+ to lumen and K+ into the cell (K+ leaks back into the lumen through leak channel)

1. on apical membrane C. Cl/HCO3- exchanges Cl- in (down gradient) for HCO3 out (as alkaline tide). Cl is

removed to lumen of stomach 1. Cl/HCO3 exchange is on basolateral membrane 2. Cl channel is on apical side

D. See Figure 9 for the picture in the lecture handout XII. Describe/diagram the changes in concentrations of Cl, H, K, and Na in gastric

juice during varying rates of gastric secretion A. Cl

1. Concentration is high regardless of secretion rate (120<) 2. highest at high rates of secretion (<140)

B. H+ 1. At low secretion rates – very low levels, close to 0 2. At high secretion rates – high (<120)

C. K+ 1. Concentration is low (<20) regardless of secretion rate 2. Highest at high secretion rates

D. Na+ 1. Highest at low secretion rates (about 80) 2. Lowest at high secretion rates (<20)

E. Pump concentrations are regulated hormonally graded reactions for varying rates of acid secretion

F. As more parietal cells are activated, more H/K ATP pumps are added to cell surfaces increases H+

G. At low secretion rates, gastric juice has high Cl and low H+ H. See figure 10 for the picture in the lecture handout


Page 116 of 168 XIII. Describe/diagram which cells gastrin, histamine, and acetylcholine act on to

induce gastric acid secretion A. Gastrin acts on parietal cells directly H+ secretion B. Histamine opens Cl channels of parietal cells K+ travels with Cl to lumen,

then recycles back to cell via H+/K+ ATPase exchanger C. ACh Acts on both ECL cells to secrete histamine and on parietal cells directly

H+ secretion XIV. Describe the structure-activity relationships for gastrin (e.g. importance of active

site and amidation of the carboxy terminus). A. Both terminal ends have an amide group on them important protector against

carboxy-peptide digestion B. Both big (G34) and little (G17) are biologically active C. Postulated that longer gastrins (less post-translational modifications) may gastric

tumors XV. Discuss the mechanisms and stimuli for release of gastrin. See LO I-B XVI. Other actions of gastrin other than regulation of acid secretion See I-B. XVII. Name the receptor on which histamine acts to induce acid secretion and

describe the second messenger system involved. A. Histamine acts on H2 receptor on parietal cells

1. Mediation by adenylate cyclase/cAMP messenger system 2. Inhibition of H2 receptors blocks acid secretion stops ulcers

1. Cimetidine blocks H2 receptors (see below, XVIII) XVIII. Discuss the rationale for the use of histamine receptor blocking agents in the

treatment of peptic ulcer disease A. Block receptor ↓ cAMP ↓ acid ↓ mucosal erosion ↓ ulcers B. Add receptor blocker (cimetidine) to increase pH in lumen C. Blocking histamine has a triple effect

1. Histamine Receptors blocked 2. ACh unpotentiated 3. Gastrin unpotentiated

XIX. Name the receptor on which acetylcholine acts to induce acid secretion and describe the second messenger system involved. A. ACh M3 type mAChR on parietal cells Second messenger system involves ⇑

intracellular Ca2+, IP3 H+ secretion 1. This represents the direct pathway of ACh’s action

XX. Describe how ACh can act indirectly to stimulate acid secretion through modulating the release of gastrin A. Vagus ACh Enteric nerve GRP binds and activates parietal cells for

acid secretion B. Vagus ACh M1 type mAChRs ECL cells histamine activate parietal

cells XXI. Discuss/diagram the three-receptor model for the interaction of ACh, histamine,

and gastrin in the regulation of acid secretion by the parietal cell A. See Figure 18 in Lecture Notes B. Potentiative interaction of the 3 major gastric regulators

1. All 3 occupy different membrane receptors in parietal cell. Because each agent has a different mechanism of action, their combined effect is greater than the sum of the individual effects

2. Blocking receptors 1. Atropine blocks ACh from binding M3 mAChRs 2. Cimetidine blocks Histamine from binding H2 receptors


Page 117 of 168 3. Blocking either receptor parietal cell’s response to all activating

agents is decreased a drug that blocks just one of these receptors is usually effective in treatment of ulcers

4. In addition, cimetidine blocks the potentiative effect itself, making cimetidine the most effective treatment for ulcers

XXII. Describe the role of enterochromafin-like cells (ECL) in the control of acid secretion A. ECL cells store Histamine B. Gastrin &ACh ECL cells release histamine acts locally on parietal cells C. Histamine release increases greatly just before acid secretion begins

XXIII. Discuss how luminal acid can inhibit acid secretion A. Decreased pH ⇓ gastrin secretion ⇓ H+ release B. Decreased pH increased somatostatin secretion inhibits parietal & G cells

XXIV. Describe the three phases of gastric acid secretion and their regulation A. Cephalic phase

1. Vagal stimulation from mouth 2. Direct stimulation of parietal cells 3. Vagal stimulation of gastrin release via GRP

B. Gastric phase 1. Starts w/ entry of bolus into stomach 2. Products of protein digestion gastrin release, 3. Gastric distention vagovagal reflex stimulates parietal cell ⇑ acid

release C. Intestinal phase

1. Starts with entry of bolus into duodenum 2. Represents ~10% of acid release 3. Mediators = duodenal gastrin, entero-oxyntin (intestinal hormone) and

circulating amino acids XXV. Describe the biochemical processes involved in pepsinogen synthesis, storage,

secretion, and activation to pepsin A. Pepsinogen isozymes 1-5 (pepsinogen I, stored in chief and mucous neck cells of

oxyntic mucosa) and isozymes 6 and 7 (pesinogen II, stored in chief and mucous neck cells of oxyntic mucous and in mucous cells of antrum and Brunner’s glands)

B. Secreted into lumen and activated by low pH chop off part of peptide to expose active site pepsin. Can be done spontaneously or by another pepsin molecule dynamic process over time

XXVI. Discuss the regulation of pepsinogen/pepsin release A. Vagal stimulation ACh-mediated B. Acidic stimulation C. Secretin simulated

XXVII. Discuss the role of intrinsic factor in the absorption of Vitamin B12 A. Intrinsic factor (IF) is released by parietal cells before acid secretion (See figure 28 in

lecture notes) B. Binds and protects vitamin from proteolysis promotes absorption in ileum C. Addressed in later LO sets

XXVIII. List the cells of origin and the chemical components of gastric mucosa A. parietal cells – HCl, intrinsic factor B. Chief cells – pepsinogen C. G cells – gastrin D. Mucous cells


Page 118 of 168 XXIX. Discuss the physiological functions and mechanisms of secretions of gastric

mucus A. Functions – protective against abrasive and acidic environment ⇓ erosion and ⇑

lubrication B. Secreted by surface mucous and mucous neck cells

1. Exocytosis – 1 granule at a time 2. Apical expulsion – entire packages at once 3. Mucous cell exfoliation (type of apoptosis) – cell turnover of entire

mucous cell layer occurs every few days XXX. (Now you know why we used roman numerals for this set). Discuss the

physiological regulation of gastric mucus secretion. A. Vagal stimulation discharge of soluble mucous from neck cells B. Mechanical stimulation noxious gelatinous mucous from surface cells C. Chemical irritant noxious gelatinous mucous from surface cells D. Gastroprotective prostaglandins made in response to noxious stimuli ⇑

mucous secretion GI Secretions III – The Pancreas 4/10/06 Dr. Lichtenberger

1. List the physiological functions of the secretions of the exocrine pancreas. a. Secretion of enzymes to hydrolyze dietary carbohydrates, proteins and lipids (this

function is essential for life). i. trypsinogen

ii. chymotrypsinogen iii. pancreatic lipase iv. amylase

b. Secretion of HCO3- both to buffer gastric acid entering the proximal intestine, and to maintain a neutral/alkaline pH in the intestinal lumen to assure optimal pancreatic enzymatic activity.

i. Secretin 1. Secreted by S cells in duodenum in response to H+ in duodenal

lumen. 2. makes pancreatic ductal cells secrete more HCO3- 3. H+ delivery from stomach to duodenum secretin release

pancreas secretes HCO3- bicarb in duodenal lumen neutralizes the H+.

2. Describe the functional anatomy of the “pancreon”. a. Anatomy:

i. Acinus – the grape-shaped secretory unit of an acinous gland 1. acinar cell – a secreting cell that lines an acinus

a. produces a small volume of initial pancreatic secretion, which is mainly Na+ and Cl- in zymogen granules

2. centroacinar cell – a nonsecretory cell of a pancreatic ductule occupying the lumen of an acinus –aka “Langerhans”

ii. Ductule – a small duct 1. duct cell – modifies the initial pancreatic secretion by secreting

HCO3- and absorbing Cl- via a Cl-/HCO3- exchange mechanism in the luminal membrane

a. because the pancreatic ducts are permeable to water, water moves into the lumen to make the pancreatic secretion isosmotic


Page 119 of 168 b. Electrolyte composition of pancreatic juice:

i. Pancreatic juice is characterized by: 1. High volume 2. virtually the same Na+ and K+ concentrations as plasma 3. Much higher HCO3- concentration than plasma 4. Much lower Cl- concentration than plasma 5. Isotonicity 6. Pancreatic lipase, amylase, and proteases

3. Discuss/diagram the steps in the synthesis and secretion of pancreatic enzymes. a. Polysomes synthesize the proteins in the acinar cells that will become the

functional enzymes of the pancreas b. These proteins are transported from the RER to the Golgi to become modified into

zymogens c. After modification, the zymogens are sent to condensing vacuoles to consolidate the

zymogens (now called a zymogen granule) d. The zymogen granule is transported to the apical surface to be secreted e. Once secreted, the zymogens become activated amylase, lipases, and proteases

close to a pH that is neutral or slightly basic 4. Discuss/diagram the steps in the secretion of bicarbonate by ductal and acinar cells.

a. CO2 diffuses from the basal side of the cell b. Carbonic Anhydrase (CA) takes H2O and CO2 and converts it to H2CO3, which

dissociates to H+ and HCO3- c. HCO3- is secreted on the luminal side by an HCO3-/Cl- antiport d. H+ is secreted on the basolateral side by an H+/Na+ antiport e. Na+/K+ ATPase regenerates Na+ gradient (which we already knew)

5. Describe the relationship between the rate of secretion of the pancreas and the ionic composition of the secretion. Explain the mechanisms for this relationship.

a. Composition of aqueous component of pancreatic secretion varies with Flow Rate i. At low flow rates, the pancreas secretes an isotonic fluid composed mainly

of Na+ and Cl- 1. Mainly Cl- in pancreatic fluid because the HCO3-/Cl- antiport on

the apical side of the duct cell is given ample time to exchange HCO3- for Cl-

ii. At high flow rates, the pancreas secretes as isotonic fluid composed mainly of Na+ and HCO3-

1. Mainly HCO3- in pancreatic fluid because exchange time is shortened (refer to Fig. 4 and 5 in handout for a visual)

iii. REMEMBER: regardless of flow rate, pancreatic secretions are isotonic 6. Describe the “cephalic phase” of pancreatic secretion in response to a meal and

discuss the mechanism of regulation of this phase. a. Cephalic Phase – represents 10-15% of the pancreatic response to feeding

i. Categorized by seeing, smelling, tasting, chewing, swallowing, hypoglycemia or thinking about food (conditioned reflex) results in the secretion of a pancreatic juice rich in enzymes.

1. “Sham feeding” can cause up to 50% of the total pancreatic secretion

ii. Mechanism of regulation: 1. Major regulation – mediated by direct efferent impulses sent by

vagal centers in the brain to the pancreas 2. Minor regulation – indirect effect of parasympathetic stimulation of

gastrin release (CCK-like effect on acinar cells)


Page 120 of 168 7. Describe the “gastric phase” of pancreatic secretion in response to a meal and

discuss the mechanism(s) of regulation of this phase. a. Gastric phase – begins when food enters the stomach and distends it

i. Represents 10-15% of the total response to feeding ii. Pancreatic secretion is then stimulated by vago-vagal reflex (process that

uses both afferent and efferent nerve fibers of the vagus nerve) iii. Gastrin-mediated pancreatic enzyme secretion

8. Describe the “intestinal phase” of pancreatic secretion in response to a meal. a. Intestinal Phase – most important phase where acidic chyme from the stomach

moves into the small intestine i. Acid in chyme stimulates release of secretin by S cells in intestinal mucosa

ii. More information in #s 10, 11 & 12 9. What are the relative importances of the cephalic, gastric, and intestinal phases in

the regulation of the pancreatic secretion? a. Cephalic Phase = 10-15% b. Gastric Phase = 10-15% c. Intestinal Phase = 70-80%

10. Describe the mechanisms regulating the release of secretin in response to a meal. a. Secretin is secreted by S cells of the duodenum in response to H+ in the duodenal

contents (pH < 4.5) and total length of intestine that is exposed to these acidified contents (total acid)

i. Acts on pancreatic duct cells to increase HCO3- secretion b. Other stimulants of secretin release

i. Fatty acids, bile salts 11. Discuss the role of secretin in regulating pancreatic bicarbonate secretion.

a. When H+ is delivered from the stomach to the duodenum, secretin is released by S cells in the intestinal mucosa. As a result, HCO3- is secreted from the pancreas into the duodenal lumen to neutralize the H+

b. Second messenger for secretin is cAMP 12. Discuss the interaction of secretin and CCK in regulating pancreatic bicarbonate

secretion. a. CCK, released by I cells in the intestinal mucosa, is stimulated by exposure of the

intestinal mucosa to long-chain fatty acids (lipid digestion products) and free amino acids

b. CCK potentiates the effect of secretin on duct cells to stimulate HCO3- secretion i. CCK is very similar in structure to secretin, which is important for the

tertiary structure 13. Explain why secretin is effective only in its intact form.

a. Every one of the 27 amino acids in secretin is necessary for it to function 14. Describe the physiological actions of CCK.

a. CCK is secreted by duodenal I cells in response to small peptides, amino acids, and fatty acids in the duodenal lumen.

b. CCK increases pancreatic acinar cell secretion of amylase, lipases, and proteases i. the second messenger for CCK is IP3 and increased intracellular

[Ca2+]. The potentiating effects of CCK on secretin are explained by the different mechanisms of action for the two GI hormones (i.e. cAMP for secretin and IP3/Ca2+ for CCK)

c. Potentiation of pancreatic HCO3 secretion d. Stimulation of gallbladder contraction e. Relaxation of the Sphincter of Oddi f. Other actions (physiological significance uncertain)

i. Inhibition of gastric emptying


Page 121 of 168 ii. Induction of satiety

iii. Stimulation of intestinal contractile activity iv. Stimulation of pancreatic growth v. Inhibition of gastric acid secretion

vi. Stimulation of insulin secretion (incretin effect) 15. Discuss the structure of CCK in terms of its “active site” and the importance of the

tyrosine sulfation. a. CCK

i. The structure of the CCK active site is similar to that of gastrin ii. 5 C-terminal amino acids are the same in CCK and gastrin

iii. the biologic activity of CCK resides in the C-terminal heptapeptide. Thus, the heptapeptide contains the sequence that is homologous to gastrin and has gastrin activity as well as CCK activity

b. Tyrosine sulfation i. A posttranslational modification of tyrosine; sulfation strengthens protein-

protein interactions. ii. some adhesion molecules, GPCRs, coagulation factors, serpins, extracellular

matrix proteins, and hormones have tyrosine sulfation iii. sulfation of cholecystokinin (CCK) is required for CCK receptor activation

1. also postulated to be involved in solubility, stabilization, and functional interaction

2. Tyrosine sulfation is necessary for CCK to be able to bind to its own receptor; otherwise it will act as gastrin!

16. Discuss the role of cholinergic nerves in the regulation of pancreatic enzyme secretion.

a. ACh, via vagovagal reflexes, is released in response to H+, small peptides, amino acids, and fatty acids in the duodenal lumen

b. ACh stimulates enzyme secretion by the acinar cells and, like CCK, potentiates the effect of secretin on HCO3- and H2O secretion.

17. Describe the interactions of stimulants of pancreatic enzyme secretion at the cellular and molecular level.

a. ACh, CCK, and gastrin act on pancreatic acinar cells i. Increase turnover IP3

ii. Release cellular calcium, which 1. depolarizes the cell 2. ↑ cGMP 3. ↑enzyme secretion

b. Secretin, VIP act on pancreatic acinar cell i. ↑ cellular cAMP,

ii. ↑ enzyme secretion 18. Describe the potentiative interaction of CCK and secretin on pancreatic bicarbonate

secretion. a. CCK slight ↑ in HCO3- secretion b. Secretin slightly higher ↑ in HCO3- secretion c. CCK + Secretin over three times as much HCO3- is released into the pancreatic

lumen i. So CCK greatly potentiates secretin

19. Explain the potential physiological importance of this potentiation. a. Potentiation is when the total is greater than the sum of its parts: the interaction of

multiple agents results in a pharmacologic response greater than the sum of the individual responses to each agent.


Page 122 of 168 b. Potentiation of CCK + Secretin ↑↑ HCO3- better prepare the small intestine

for the chyme c. This potentiation is explained by different mechanisms of the two GI hormones

(secretin uses cAMP and CCK uses cGMP) 20. Discuss the possible mechanism for the inhibitory effect of intraluminal trypsin and

its possible degradative effect on CCK-Releasing Peptide on pancreatic secretion. a. Trypsinogen produced by the pancreas is activated to trypsin by a brush border

enzyme, enterokinase b. Trypsin then converts chymotrypsinogen, proelastase, and procarboxypeptidase A

and B to their active forms (even trypsinogen is converted to more trypsin by trypsin!)

c. After their digestive work is complete, the pancreatic proteases degrade each other and are absorbed along with dietary proteins.

d. Intraduodenal trypsin inhibits pancreatic secretion mediated by CCK 21. Discuss the potential role of peptide YY (PYY) and of pancreatic polypeptide (PP) in

inhibiting pancreatic secretion. a. PP inhibits pancreatic enzyme output & gallbladder contraction

i. PP is responsible for coordinating exocrine and islet enzyme release b. The distal gut hormone peptide YY (PYY) mediates feedback inhibition of gastric

acid secretion, gastrointestinal motility, and pancreatic enzyme output. PYY is released in proportion to calorie intake, and it inhibits eating.

i. PYY acts on the pancreas to increase its secretion of digestive juices and on gallbladder to stimulate the release of bile

c. Sham feeding makes both of these proteins plus NPY increase i. In comparing sham feeding to actual feeding, PP is released in significant

amounts during actual feeding 22. Explain why insulin release is greater after oral glucose as compared to an

intravenous glucose, and how this fits into the concept of an incretin. a. Release of Glucose-dependent insulinotropic peptide (GIP)

i. Stimulated by the presence of glucose or fat in the intestinal lumen NOT by glucose in the blood

ii. May inhibit gastric acid secretion iii. Causes insulin release

b. Release of insulin i. Only slightly stimulated by glucose in blood

ii. Heavily stimulated by oral glucose c. A comparable rise in blood glucose by IV infusion of the sugar has little stimulatory

effect on the blood levels of either insulin or GIP d. Incretins are hormones that increase insulin release and decrease glucagon release

in response to sugar intake – that act before blood glucose levels elevate. They reduce gastric emptying, slow nutrient absorption and reduce food intake. If these hormones generally work before blood glucose levels elevate, it fits together with their mechanism that oral ingestion initiates a pathway that IV glucose does not.

23. Discuss the possible insulin – stimulatory (incretin) roles of GIP and enteroglucagon / glucagon-like peptide (GLP-1).

a. GIP – stimulated by the presence of glucose or fat in the intestinal lumen i. Was thought to inhibit gastric acid secretion (entero-gastrone effect)

ii. Is now thought to cause insulin release (incretin) b. GLP-1

i. Stimulates insulin release (incretin) ii. 50% of the body’s store of glucagon is present in the intestine

iii. Shares many actions with secretin, glucagon and GIP


Page 123 of 168 GI Secretions IV: The Liver and Biliary System Lichtenberger April 11, 2006

1. Biliary Secretion a. Bile is formed by the liver epithelial cells (hepatocytes) and by epithelial lining the

bile ducts, called ductal cells. Between 250-1100 mL of bile are secreted daily b. Synthesis, 0.2-0.6 g/day c. Biliary Secretion = 12-36 g/day d. Fecal Excretion = 0.2-0.6 g/day e. Urinary excretion = <0.5 mg/day f. Portal venous return >95% of biliary secretion

2. List the physiological functions of bile a. Bile is required for the digestion and absorption of lipids in the intestinal lumen b. Bile serves as a vehicle for the elimination of endogenous (cholesterol, bile

pigments) and exogenous (drugs, metals) substances from the body 3. Describe the functional anatomy of the Biliary tract/gallbladder system

a. Bile is secreted by the hepatocytes into the bile canaliculi b. Bile flows in the ductules and ducts, lined by biliary epithelium c. Bile flow through the canaliculi runs counter to the flow of blood through the

hepatic sinusoids assuring efficient extraction of bile acids by the hepatic parenchymal cells and secretion into the canaliculi

d. Bile flows through canaliculi into the bile ductile bile duct common bile duct sphincter of Oddi

i. Between meals (interdigestive period) the Sphincter of Oddi is closed so there is retrograde flow of bile into the cystic duct gallbladder, for storage

4. List the organic components of bile a. Bile Acids (BA-), constitute 50% of solids

i. Primary Bile acids 1. Cholic acid (trihydroxycholic acid) 2. Chenodeoxycholine acid (dihydroxychenodeoxycholic acid)

ii. Secondary Bile acids 1. Deoxycholic acid 2. Lithocholic acid (monohydroxy acid)

b. Phospholipids (30-40% of the solids), are normally insoluble in water, so they are solubilized by the bile salt micelles

i. Lecithin/phosphatidylcholine represent the major components c. Cholesterol (4%) of the solids), is essentially insoluble in water and thus must be

solubilized by bile salt micelles (addressed later) before it can be secreted in the bile d. Bile Pigments (2% of solids)

5. Explain the difference between a “primary” and a “secondary” bile acid a. Primary Bile acids are synthesized from cholesterol and converted by the

hepatocytes into bile salts b. Secondary Bile acids are formed by deconjugation and dehydroxylation of the

primary bile salts by intestinal bacteria 6. Discuss the importance of conjugation of bile acids with glycine and taurine

a. Secondary bile acid are conjugated to glycine (Deoxycholic acid) or taurine (Lithocholic acid) in order to remain soluble in bile secretion

b. Unconjugated bile acid’s buffering capacity is best at pH =5-7 if pH falls bellow that, they would precipitate out of solution


Page 124 of 168 c. Conjugated bile acids have a much lower pKa and are more completely ionized

making them more water soluble and thus they stay in solution when secreted at physiological pH

7. Describe bile acid biosynthesis, the rate-limiting enzyme in the synthesis of bile acids and how it is regulated

a. Bile acids are derivates of cholesterol i. 7�-hydroxylase catalyzes the formation of cholesterol to bile acid (e.g.

cholic acid) intermediates ii. The 7� hydroxylation step is rate-limiting iii. This step is inhibited by bile acids which have been taken up by the

hepatocytes from the portal blood, thereby stopping bile acid synthesis 8. Describe the amphipathic properties of bile acids, and their role in lipid

emulsification and digestion a. Bile salts are amphipathic molecules because they have both hydrophilic and

hydrophobic portions b. In aqueous solution, bile salts orient themselves around droplets of lipid and keep

the lipid droplets dispersed (emulsification) c. Bile salts thus aid in the intestinal digestion and absorption of lipids by emulsifying

and solubilizing them in micelles 9. Describe a “micelle,” list the components of a “mixed micelle,” and discuss the

properties of micelles in lipid absorption a. Above a critical micellar concentration (CMC), bile salts form micelles b. Bile salts are positioned on the outside of a micelle, with their hydrophilic portions

dissolved in the aqueous solution of the intestinal lumen and their hydrophobic portions dissolved in the micelle interior

c. Free fatty acids and monoglycerides are present in the inside of the micelle, essentially “solubilized” for subsequent absorption

d. Mixed micelles, composed of bile salts and phospholipids are able to solubilize other lipids more effectively than when they are composed of bile salts alone because phospholipids can bind to the lipid itself (it’s sortof stickier)

e. Micelles bring the products of lipid digestion into contact with the absorptive surface of the intestinal cells

10. Describe the major steps in the catabolism of hemoglobin to bile pigment a. Hemoglobin is metabolized into bilirubin and biliverdin (the two principal bile

pigments) in the liver and conjugated as glucoronides from excretion b. Intestinal bacteria metabolize bilirubin further to urobilin, which is responsible for

the brown color of stool c. If bilirubin is not secreted by the liver, it builds up in the blood and tissues,

producing jaundice 11. Contrast the composition of hepatic bile and gallbladder bile in terms of electrolyte

composition and osmolality a. Hepatic bile has a water and electrolyte concentration that equals that of plasma

i. Na+ = 140-150, K+ = 4.0-4.5, Cat+ = 2.5-4, Cl- = 80-100, HCO3 =25 b. Gallbladder bile, however, is more concentrated than plasma

i. Gallbladder concentrates bile by absorbing Na+, Cl-, HCO3-, and water from the bile, increasing the bile acid concentration 5-20 fold

ii. Na+ = 300, K+ = 10, Cat+ = 2.0, Cl- = 5, HCO3 = 12 12. Explain why the osmolality of gallbladder bile is not as great as expected from its

ionic composition a. The osmolality of bile is less than its molality because the micellar properties of a

bile salt solution results in the formation of macromolecular ion complexes


Page 125 of 168 b. Concentration of bile in the gallbladder can be explained by the absorption of an

isotonic solution of NaCl and NaHCO3, leaving what is essentially a concentrated but isoosmotic solution of sodium bile salts

c. The sum of hydrostatic and osmotic pressures in the intraepithelial space, interstitium, and capillaries favors fluid absorption from the gallbladder lumen, thus concentrating the organic components of bile 5-20 fold

13. Describe the role of bile acids in stimulating bile flow (bile-acid-dependent secretion)

a. The bile-dependent secretion refers to the quantity of bile salts secreted by the liver b. The amount of bile salts secreted is directly related to the amount of bile reabsorbed

by the hepatocytes (i.e. the more bile reabsorbed from the portal circulation, the more bile secreted by the liver)

i. The total amount of bile is relatively constant the liver has a limited synthetic capacity, there is a limit to the amount of bile that can be secreted

ii. Substances that enhance bile secretion are called choleretics Bile salts and bile acids are the major choleretics

1. That makes bile salts their own biggest fans 2. To be a choleretic, you have to work on the liver directly

iii. The synthesis and secretion of bile by the liver is not under any direct hormonal or nervous control

14. Describe the role of secretin in stimulating biliary bicarbonate secretion and flow (bile-acid-independent secretion)

a. The bile-acid-independent secretion refers to the amount of fluid, composed of electrolytes and water, that is secreted each day by the liver

b. Secretion of this fluid is controlled by the hormone secretin c. This fluid has a high concentration of HCO3-

15. Describe fluid reabsorption by gallbladder, and its role in concentrating the organic constituents of bile

a. See #12 a-c 16. Discuss the role of CCK and nerves in bringing about gallbladder contraction and

sphincter of Oddi relaxation in response to a meal a. CCK is the major stimulus for gallbladder contraction and sphincter of Oddi

relaxation i. When chyme enters the small intestine, fat and protein digestion products

directly stimulate the secretion of CCK b. Vagal stimulation of the gallbladder also causes gallbladder contraction and

sphincter of Oddi relaxation i. Vagal stimulation occurs directly during the cephalic phase of digestion and

indirectly via a vagovagal reflex during the gastric phase of digestion 17. Describe the enterohepatic circulation of bile acids. Include passive as well as active

mechanisms. a. Enterohepatic circulation recirculation of bile salts from the liver to the small

intestine and back again. This circulation is necessary because of the limited pool of bile salts available to help break down and absorb fat

b. Intestinal transport of bile acids (>95% of all bile acids are reabsorbed by the small intestine)

i. Passive transport of deconjugated bile acids occurs in jejunum and ileum 1. Bacteria in terminal part of ileum and colon deconjugate bile acids

and also dehydroxylate them to produce secondary bile acids both deconjugation and dehydroxylation lessen the polarity of bile acids, thereby enhancing their lipid solubility and their absorption by simple diffusion


Page 126 of 168 ii. Active transport of conjugated bile salts occurs in the ileum

1. Na+ coupled secondary active transport, are present on brush border of terminal ileum for uptake of conjugated bile acids against a large concentration gradient

18. Discuss the effect of the enterohepatic circulation on bile acid synthesis and conservation.

a. Bile acids, whether absorbed by active transport or simple diffusion, are transported away from the intestine in the portal blood, mostly bound to albumin in plasma

b. In the liver, hepatocytes avidly extract the bile acids from the portal blood i. In a single pass through the liver, the portal blood is cleared of the majority

of acids ii. Bile acids in all forms, primary and secondary, conjugated and

deconjugated, are taken up by hepatocytes iii. Hepatocytes reconjugate nearly all the deconjugated bile acids and

rehydroxylate some of the secondary bile acids these bile acids are secreted into the bile along with newly synthesized bile acids

c. The circulating pool of bile salts (primary and secondary acids) is approx. 3.6g 4-8g required to digest and absorb a meal total pool of salts must circulate twice during digestion of each meal bile salts usually recirculate 6-8 times daily

d. Rate of bile salt synthesis is determine by rate of return to liver Synthesis rate = 0.2-0.4 g/day, which replaces normal fecal losses

19. Discuss in general terms; the pathogenic mechanism(s) of gall stone formation and jaundice.

a. Gallstones are chiefly composed of cholesterol; the remainder are pigment stones, composed chiefly of calcium bilirubinate

i. Cholesterol is insoluble in water when bile contains more cholesterol than can be solubilized in the bile acid phospholipids micelles crystals of cholesterol form in the bile bile is supersaturated with cholesterol and stones form

ii. Bile pigment stones mainly comprised of calcium salt of unconjugated bilirubin Induced by bacterial deconjugation of bilirubin glucoronides

b. Jaundice (a.k.a. cholestasis) a condition where bile cannot flow from the liver to the duodenum Can be due to biliary obstruction by mechanical means or by metabolic factors in hepatocytes accumulation of bilirubin in the bloodstream and subsequent deposition in the skin causes jaundice (icterus)

20. Discuss the effect of ileal resection on the enterohepatic circulation, bile acid synthesis, gallstone formation and lipid absorption

a. Disruption of the enterohepatic circulation i. ileal resection or small intestinal disease such as sprue or Crohn’s disease

1. Celiac sprue is a disease of the intestinal mucosa; it causes protein sensitivity and is treated by putting the patient on a gluten-free diet

ii. Leads to decreased bile acid pool and malabsorption of fat and fat-soluble vitamins

iii. Clinical manifestations Steatorrhea and nutritional deficiency iv. Increase in fecal losses of bile salts results in watery diarrhea, because bile

salts inhibit water and Na+ absorption in the colon v. Removal of distal ileum decreases the rate of return of bile acids in he

portal blood, resulting in a much greater rate of synthesis of bile acids vi. Formation of cholesterol gallstones occurs with ileal resection

presumably due to the increased synthesis of bile and potential to become supersaturated leading to stone formation


Page 127 of 168 GI Digestion and Absorption I: Small Intestine, Part I April 17, Abdulnour-Nakhoul Functional anatomy, digestion and absorption of carbohydrates and proteins

1. Relationship between surface area and gross/microscopic anatomy of the small bowel

a. Mucosal surface area can be amplified to form specialized features i. circular folds increase surface area X3 ii. villi X 30 iii. microvilli X600

2. Major functions of small intestine a. Mixing and propulsion of luminal contents b. secretion of hormones c. secretion of mucous d. digestion e. absorption

3. Major starches, disaccharides and monosaccharides a. Starches – about 55-60% (220-240g per person) of consumed carbohydrate (total

average daily consumption is 400g) i. amylopectin

1. plant starch 2. glucose polymer with α 1-6 and α 1-4 linkages

ii. amylose 1. glucose polymer with α 1-4 linkages

iii. cellulose 1. plant starch 2. glucose polymer with β 1-4 linkages

iv. glycogen 1. animal starch

v. α-amylases from the saliva and pancreatic secretions hydrolyze 1,4 bonds to yield maltose, maltotriose and alpha-limit dextrins

vi. maltase, α-dextrinase and sucrase in the intestinal brush border hydrolyze these oligosaccharides to glucose

b. Dissaccharides i. sucrose

1. 30% of intake (120g) 2. sucrase glucose and fructose

ii. lactose 1. 6% of intake (24g) 2. lactase glucose and galactose

a. Absence of lactase in the brush border leads to lactose intolerance, producing osmotic diarrhea in reaction to lactose consumption.

iii. maltose 1. 2% of intake (8g) 2. Glucose dimers 3. maltase glucose

iv. Trehalose 1. α 1-1 glucose 2. trehalase glucose

c. Monosaccharides: ONLY monosaccharides can be absorbed


Page 128 of 168 i. Glucose ii. Fructose iii. Galactose

4. Most important brush border oligosaccharides a. Glucose/Galactose carrier

i. SGLT1: Sodium/Glucose cotransporter ii. Sodium gradient provides energy for sugar entry into intestinal epithelial

cells 1. Therefore sodium/potassium pump inhibitors also inhibit glucose

and galactose absorption b. Fructose carrier

i. GLUT 5: Glucose transporter 1. Facilitated diffusion – cannot be absorbed against a concentration

gradient that does not favor absorption c. Basolateral transport

i. Fructose, Glucose and galactose all leave basolateral membrane by GLUT2 1. Facilitated diffusion

5. The substrate that is co-transported by both SGLT and most amino acid carriers a. Cabaret lied to us. It’s sodium that makes the world go around.

6. Features of peptide vs. carbohydrate transport across brush border membrane a. Protein:

i. normal consumption is 70-90g/day ii. adequate intake is 35-50g/day but it also needs to cover all of the essential

amino acids iii. 60% of ingested protein has to be broken down before absorption

1. free amino acids, di- and tripeptides are digestible 2. Intracellular peptidases break down larger peptides

a. endopeptidases hydrolyze interior peptide bonds b. exopeptidases hydrolyze one amino acid at a time from the

end of the peptide (at the C-terminus, “carboxy” or N-terminus “amino” side)

iv. Amino acid transport 1. some basolateral diffusion 2. At least 3 Na+-independent amino acid transporters in the

basolateral membrane a. Na+-dependent

i. Neutral ii. Acidic iii. Imino

b. Na+-independent i. Neutral ii. Basic iii. Larger/hydrophobic

3. amino acid carriers: a. Neutral or�� amino mono carboxylic

i. aromatics 1. F, Y, W

ii. aliphatics 1. G, V, I, L, S

iii. H, M, N, Q, C, P, OH-P


Page 129 of 168 iv. Autosomal recessive defect in neutral amino acid

carriers Hartnup disease: Tryptophan can’t diffuse Pellagra

b. Basic or cationic i. K, R, Ornithine, C ii. Impairment of these channels cystinuria

c. Acidic or anionic i. D, E

d. Imino i. P, OH-P, GABA, Taurine, G

4. Oligopeptide transporters: a. Family: proton-dependent oligopeptide transporters aka

POT or PTR i. Broad selectivity for di- and tripeptides ii. Most of these transporters have a similar

structure, with 12 transmembrane domains iii. Example: PepT1 – main intestinal H+/dipeptide

transporter protein. Plays critical role in oral bioavailability of peptidelike drugs.

b. Major differences between carbohydrate and protein absorption: i. Polymer absorption

1. Proteins can be absorbed as amino acids, dipeptides, tripeptides 2. Carbohydrates can only be absorbed as monosaccharides

ii. Carriers 1. Amino acids carriers are charge-specific – therefore 4 types

GI Digestion and Absorption Part II: Small Intestine Part II April 18, 2006 Dr. Abdulnour-Nakhoul

1. Define the role of micelle formation in lipid digestion a. Mixed micelles are spherical (usually) formations with free fatty acids in the interior

and bile acids on the surface. Micelles serve to bring products of lipid digestion into contact with the absorptive surface of the intestinal cells.

i. 2-monoglycerides, esp. cholesterol and lysolecithin, are the fats that wind up in micelles – NOT triglycerides

b. Mixed micelles allow lipids to move through the unstirred water layer – this is the rate-limiting step in fat absorption, because once through the unstirred water layer, the fatty acids are able to easily diffuse through the plasma membrane of cells lining the small intestine

c. Bile acids emulsify lipids by allowing them to form mixed micelles, which are relatively small units – so the surface area is increased

d. Bile acids are amphipathic 2. Define the major steps involved in lipid absorption

a. Visit McDonald’s, consume copious fat products b. Fat in the duodenum release of CCK gallbladder contraction, Oddi relaxation c. Pancreatic lipases are released Cleave fat Cholesterols, glycerols, fatty acids are

separated out Bile acids emulsify fats micelles form diffusion through unstirred water micelles unform fats diffuse into cells

d. In the intestinal cells, the products of lipid digestion are re-esterified to triglycerides, cholesterol esters and phospholipids


Page 130 of 168 e. Phospholipids + apoproteins Chylomicrons are exocytosed into the lymphatic

vessels f. If you’re missing apoproteins no chylomicrons “Abetalipoproteinemia” – a

disease where you can’t digest fat (I wish) but you also can’t absorb fat-soluble vitamins, often leading to Vitamin E deficiency

3. Describe the role of intrinsic factor in the utilization of dietary cobalamin (B12) a. In the small intestine, pancreatic proteases digest binding proteins from the chyme,

releasing vitamin B12 (cobalamin) b. Parietal cells from the corpus of the stomach release intrinsic factor, a glycoprotein

i. In a gastrectomy, you lose your parietal cells and then you have to get B12 shots like Courtney Love

c. R protein, found in saliva, binds to B12 in the stomach R is cleaved off by pancreatic enzymes intrinsic factor binds in R’s place absorption is facilitated

i. At acid pH, which is obviously how life in the stomach is, R has a higher affinity for B12 – but in the small intestine, where pH is higher, intrinsic factor has a higher affinity for B12.

ii. Change in affinity status facilitates change in protein bound to B12 iii. Receptors in the Ileum recognize intrinsic factor B12 bound to intrinsic

factor gets absorbed iv. B12 is important for the maturation of erythrocytes

1. Loss of B12 pernicious anemia a. secondary to atrophy of gastric mucosa

4. Describe the mechanisms of calcium absorption within the brush border and basolateral membranes of the enterocyte

a. Brush border i. Crosses through calcium channel ii. Facilitated by Vitamin D (produced in kidney)

b. Inside cell i. Binds to calbindin or is packaged into vesicles

1. Vitamin D promotes the synthesis of calbindin (most important action of Vitamin D)

c. Basolateral membrane i. Calcium in vesicles is released by exocytosis ii. Calcium-Hydrogen ATPase antiporter iii. Calcium-Sodium antiporter iv. Calbindin facilitates

d. More information i. Calcium is absorbed throughout the small intestine, but is only actively

transported into the cells in the duodenum ii. Passive paracellular diffusion of calcium also contributes to absorption iii. Increased acidity of the GI tract increases absorption

1. Calcium citrate is more effectively absorbed 2. Vitamin C helps you absorb calcium 3. Drink your milk, eat your vegetables.

iv. Vitamin D deficency or chronic renal failure results in inadequate intestinal calcium absorption rickets in children, osteomalacia in adults

5. Describe the mechanism of iron absorption and storage in the enterocyte a. Average daily intake of iron is 10-20 mg b. Approximately 10% of the iron entering the digestive system is absorbed c. Most of the iron we consume is bound to hemoglobin or myoglobin from animal

meat (because we eat the muscle and there’s blood in there) i. Heme iron is the form found in these globins


Page 131 of 168 d. Other iron we absorb is free iron Fe2+

i. transported in blood, while bound to transferrin e. Inside epithelial cells: 2 pools of iron

i. 1 pool of iron available for absorption into blood 1. in blood, free iron is bound to transferrin

a. transferrin transports iron from the small intestine to its storage sites in the liver, and from the liver to the bone marrow for hemoglobin synthesis

ii. second pool is bound to ferritin within epithelial cells 1. This process makes the iron unavailable for transport across the

basolateral membrane 2. This iron is lost into the lumen when the epithelial cell is sloughed

off – preventing excessive iron absorption f. Iron deficiency is the most common cause of anemia

6. Identify the luminal and basolateral ion transporters involved in electrolyte secretion across the epithelial cells in the crypt of Lieberkuhns

a. Luminal i. Chloride enters the lumen via an electrogenic channel (actively, powered by

sodium gradient) results in negative luminal charge results in sodium secretion into lumen (partly via tight junctions)

1. Water follows to maintain isoosmoticity b. Basolateral

i. Na/K/2Cl cotransporter ii. Potassium leaves the cell via potassium channels, facilitated by calcium and

cAMP GI Digestion and Absorption III: Large Intestine April 19, 2006 Dr. Abdulnour-Nakhoul

1. Components contributing to fluid load presented to the colon a. Ingestion – 2000 ml/day b. GI tract secretes 7L/day

i. Saliva – 1500 ml/day ii. Gastric secretion – 2000 ml/day iii. Bile – 500 ml/day iv. Pancreatic Juices – 1500 ml/day v. Intestinal secretions – 1500 ml/day

c. Small intestine absorbs 8500 ml/day d. Colon absorbs 80-90% of the 500 ml passed to it e. And the rest comes out fine in the end.

2. 4 major groups of sodium transporters present in the large and small intestines a. luminal

i. SGLT 1 - Na/glucose cotransporter 1. Jejunum 2. Ileum

ii. Na/amino acid cotransporter 1. Jejunum 2. Ileum

iii. Na/H antiporter 1. Jejunum 2. Ileum


Page 132 of 168 3. Colon

iv. Na/Cl cotransporter 1. BRS doesn’t say where.

v. Sodium channel 1. Passive diffusion 2. Colon

b. Basolateral i. Na/HCO3 cotransporter (both into cell)

1. Ileum 2. Colon

ii. Na/K ATPase 1. Everywhere

c. And by 4, we mean 7. 3. Relationship between fluid and electrolyte absorption

a. Water absorption is secondary to solute absorption maintains tonicity 4. Transporters directly influencing pH of large and small intestines

a. H+ transporters i. Na/H antiporter – H goes into the lumen

1. Jejunum 2. Ileum 3. Colon

ii. K/H ATPase – active pump because lumen is negatively charged - H goes into the cell

1. Colon b. HCO3 transporters

i. Bicarb/Cl antiporters 5. ATPase responsible for hydrogen secretion in the stomach and potassium absorption

in the colon a. We don’t know how to answer this question because potassium is secreted in the

colon. Geesh. They must mean K/H ATPase antiports. i. In the stomach, H goes into the lumen while K goes into the cell (parietal

cells) 1. Believe it or not, some potassium is also secreted in the stomach

(also by parietal cells) ii. In the colon, K goes into the lumen while H goes into the cell

6. Factors controlling salt and water transport in the gut a. Endocrine control (all promote net absorption)

i. Aldosterone 1. >Epithelial Na Channels (ENaC) 2. Na/K ATPase

ii. Glucocorticoids 1. Na/K ATPase

iii. Epinephrine 1. >NaCl absorption

iv. Angiotensin II 1. >NaCl absorption

b. Paracrine (all promote net absorption) i. Somatostatin

1. >absorption, <motility ii. Opioids

1. >absorption, <motility c. Neural regulations


Page 133 of 168 i. Enteric – promotes net secretion

1. Gut distension, luminal glucose, acid pH 2. Acetyl choline 3. Vasoactive intestinal peptide (VIP) 4. Secretin

ii. Parasympathetic – promotes net secretion 1. Cholinergic

iii. Sympathetic – promotes net absorption 1. Catecholamines 2. Alpha-adrenergic

d. GI Immune system (all stimulate net secretion) i. Histamine – secreted by enterochromaffin-like cells ii. Serotonin iii. Prostaglandins iv. Leukotrienes v. Arachidonic acid vi. Nitric Oxide

e. Bacterial enterotoxins – stimulate net secretion i. Cholera, E Coli, Chlostridium

f. Laxatives – stimulate net secretion i. Bile acids, ricinoleic acid

7. 5 Major components of feces a. Bacteria 30% b. Undigested fiber 30% c. Lipids 10-20% d. Organic matter 10-20% e. K+ and Bicarb

8. Major components of gas in the GI tract a. Swallowed air b. CO2 from HCO3/H combination c. Volatile products of bacterial digestion d. Diffusion from blood to lumen

Block IV: Endocrine LOs for May 1st: Endocrine Hormones – Structure-function and mechanisms

1. Hormone classification and properites & overall functioning of endocrine system a. A hormone is a chemical substance produced by specialized cells, often carried by

the bloodstream to act on distant target cells. b. A hormone binds to a receptor on a cell, eliciting a specific response within that cell. c. Hormones effect homeostasis, regulate processes of growth and development,

reproduction, and senescence (the process of aging). 2. Classify and differentiate between endocrine, paracrine, autocrine and neurocrine

hormone actions a. endocrine: secreted into body fluids and acts away from its point of origin b. paracrine: secreted and acts close to its point of origin (neighboring cells) c. autocrine: acts on its own source (on the actual cell that secreted it) d. neurocrine: secreted by a nerve ending and acts on non-nervous tissue e. neurotransmission (for Sara): secreted by a nerve ending and acts on another neuron


Page 134 of 168 f. These words describe actions, not hormones’ identities; any given substance can act

in more than one of these capacities. 3. know the major endocrine glands and depict the structure-function relationship of

various hormones a. Classic endocrine glands

i. anterior pituitary 1. adrenocorticotropic hormone (ACTH)

a. ↑ steroid hormone synthesis in the adrenal cortex b. Hypothalamus Corticotropin releasing hormone (CRH)

Anterior pituitary ACTH Adrenal Cortex Cortisol Hypothalamus and Anterior Pituitary

2. growth hormone (GH) a. GH IGF

i. IGF makes you grow, ↑ protein synthesis in muscle ↑in lean body mass, ↑ organ size

b. Hypothalamus GHRH [Ant pit GH] [Hypothalamus Somatostatin] [Ant Pit GH]

3. prolactin (PRL) a. Lactogenesis b. PRL + estrogen boobies c. homologous to GH d. Hypothalamus Thyrotropin releasing hormone (TRH)

Ant Pit Prolactin [Hypothalamus Dopamine] [Ant Pit PRL]

i. This action of dopamine makes it an important prolactin inhibiting factor or PIF

4. thyroid stimulating hormone (TSH) a. Thyroid hormones secreted due to this pathway promote

growth, bone formation, bone maturation, and are involved in CNS, ↑Basal metabolic rate, CV and respiratory system (↑ CO and respiratory rate), etc

b. Hypothalamus TRH Ant Pit TSH Thyroid T3, T4 Ant Pit

5. luteinizing hormone (LH) a. Ovulation, corpus luteum, estrogen and progesterone b. In males, synthesis and secretion of testosterone in the

testis c. Ant Pit LH Ovaries secrete estrogen estrogen

anterior pituitary releases LH i. only works during periods of high estradiol, on

day 15 of the menstrual cycle ii. Only positive feedback we’ve seen iii. Sorry, I meant to say you’re doing great!

6. follicle-stimulating (FSH) a. Stimulates maturation of ovum (i.e., follicle) b. In males, spermatogenesis c. In females: Hypothalamus GnRH Ant Pit FSH

& LH Ovary Estrogen & Progesterone [Ant Pit FSH & LH]


Page 135 of 168 d. In males: Hypothalamus GnRH Ant Pit FSH

Sertoli cells maintain spermatogenesis, secretion of inhibin [Ant Pit FSH]

ii. posterior pituitary 1. vasopressin (ADH)

a. ADH increases water permeability of the principal cells of the late distal tubule and collecting duct

b. ADH constricts vascular smooth muscle c. Factors that ↑ADH:

i. ↑ serum osmolarity ii. blood volume decrease (“contraction”) iii. hypoglycemia iv. nicotine and opiates

d. Factors that ↓ADH: i. ↓serum osmolarity ii. ethanol iii. ANP iv. alpha-adrenergic agonists

2. oxytocin a. causes ejection of milk from the breast

i. stimulated by suckling, and psychological factors relating to the presence of a baby

b. stimulates uterine contractions c. in men, oxytocin is also released. also from suckling and

related activites. i. function unknown, may be related to ejaculation

iii. Thyroid gland 1. thyroxine (T4) – see TSH 2. triiodothyronin (T3) – see TSH 3. calcitonin

a. produced by C cells of the thyroid b. reduces blood calcium

i. ↓intestinal absorption of calcium ii. ↓osteoclast activity in bones iii. decreasing calcium and phosphate reabsorption in

kidney tubules c. responds to ↑ plasma calcium

iv. Parathyroid glands 1. parathyroid hormone (PTH)

a. Secreted by chief cells of parathyroid glands b. ↑ plasma calcium concentration

i. binds to osteoblasts osteoclasts stimulated bone breakdown ↑plasma calcium concentration

v. testes 1. testosterone

a. synthesized by leydig cells in the testes b. secondary sexual characteristics in men c. LH Leydig cells testosterone [anterior pituitary

LH]


Page 136 of 168 i. only unbound testosterone has this suppressive

effect vi. ovaries

1. estradiol a. from granulosa cells of ovaries b. growth and development of female reproductive organs,

secondary female characteristics, increased bone density c. controls follicular phase of menstrual cycle, thickening of

endometrium d. estradiol [hypothalamus GnRH Ant pituitary

LH, FSH] i. this is the basis of oral contraceptives

2. progesterone a. controls luteal phase of the menstrual cycle b. released by placenta during pregnancy helps maintain

pregnancy by maintaining endometrium c. progesterone [hypothalamus GnRH Ant

pituitary FSH & LH] i. present in oral contraceptives because unopposed

estrogen would increases the risk of uterine cancer 3. shout out to Pamela Jones!

vii. pancreas 1. insulin

a. released in presence of blood glucose b. � cells in pancreas

i. Glucose GLUT 2 receptors ↑ ATP closes potassium channels no more K+ in depolarization open calcium channels more calcium influx vesicular release of insulin

c. ↓blood glucose, fatty acids and amino acids d. in starvation # of receptors ↑ e. in gluttony # of receptors decreases f. 3 ways insulin decreases blood glucose:

i. ↑ uptake ii. promotion of glycogen formation iii. ↓gluconeogenesis

2. glucagon a. released from α cells b. primarily acts on hepatic and adipose tissue c. ↑ blood glucose

i. glycogenolysis ii. ↑ gluconeogenesis

3. somatostatin a. delta cells b. glucagon, insulin, gastrin

b. Non-classic endocrine glands i. hypothalamus

1. releasing and inhibiting hormones – GHRH, LHRH, TRH, CRH…as per section a of this question

ii. heart


Page 137 of 168 1. atrial natriuretic peptide

a. blood pressure right atrium ANP Na+ excretion osmotic water excretion ↓blood volume ↓blood

pressure iii. kidney – see block II. Honestly, now.

1. erythropoietin 2. renin

iv. liver 1. insulin-like growth factor “IGF-1”

a. covered under GH v. platelets

1. platelet-derived growth factor – PDGF a. regulates cell growth and division

2. transforming growth factor β – TGF β vi. macrophages

1. cytokines a. signalling particles for immune response

vii. gastrointestinal tract – see block III. 1. gastrin 2. secretin 3. VIP

c. structure-function relationships i. proteins and polypeptides

1. generally water-soluble 2. circulate unbound in plasma 3. vary greatly in size, weight etc.

ii. amino acid derivatives 1. catecholamines are water-soluble

a. derived from tyrosine 2. thyroid hormones are lipid-soluble

a. derived from two iodinated tyrosine residues b. the only substances in the body that contain iodine

i. salt is iodinated so that we can produce TH 3. circulate in plasma, bound mainly to binding globulins

iii. steroid hormones 1. lipid-soluble 2. circulate in plasma, bound to carrier proteins (steroid-binding

globulins) 4. Feedback regulation of hormone production

a. Positive feedback: i. When presence of a substance leads to an increase in the release of the

same substance ii. Only example we’ve learned is LH

b. Negative feedback: i. When presence of a substance leads to a decrease in the release of that

substance. This is often accomplished, as we saw in biochem, via inhibition of the pathway leading to the production of that substance.

1. See throughout list of hormones for their individual negative feedback mechanisms – hopefully this was already obvious, but I’ve shown inhibition as

5. Mechanisms of action of hormones and hormonal cascades


Page 138 of 168 a. See answer to Question 1

6. Whole-body responsiveness to hormones a. Hormonal control is dependent on receptors. Receptor types are what determine

body response. So the extent of hormonal influence is based on which receptors are present throughout the body.

b. This may or may not be what Pandey meant for us to respond. If anyone has ideas on what this question means, feel free to share.

7. Plasma binding proteins, free hormones, inactivation/degradation & excretion a. Plasma binding proteins bind hormone turnover rate of hormone b. metabolic clearance rate

i. MCR = mg/min removed / mg/ml plasma = ml plasma cleared / min ii. Kidney and liver are the major sites of metabolic degradation of hormones

c. Breakdown pathways: i. proteolysis, oxidation, reduction, hydroxylation, decarboxylation,

methylation d. **We’re still trying to figure out what the specific mechanism of action of the

plasma binding proteins is, and how it relates to inactivating hormones, but in general, plasma binding proteins bind to hormones, and it changes the delivery of hormones to the tissues. If you know more than this, please let me know.

8. explain the methodologies to measure hormone production a. Radio Immunoassay (RIA)

i. good for very small quantities ii. measures antigenic amounts of hormone – may even be sensing an amount

below the threshold of biological activity iii. Technique:

1. A mixture is prepared of a. radioactive antigen

i. Because of the ease with which iodine atoms can be introduced into tyrosine residues in a protein, the radioactive isotopes 125I or 131I are often used.

b. antibodies against that antigen. 2. Known amounts of unlabeled ("cold") antigen are added to

samples of the mixture. These compete for the binding sites of the antibodies.

3. At increasing concentrations of unlabeled antigen, an increasing amount of radioactive antigen is displaced from the antibody molecules.

4. The antibody-bound antigen is separated from the free antigen in the supernatant fluid, and the radioactivity of each is measured.

b. Enzyme-linked immunosorbent assay (ELISA) i. It’s basically the same thing except that you use a chromogenic or a

fluorogenic marker, which fluoresce under UV light ii. You don’t use radiolabels, so you won’t create radioactive labtechs iii. this is what people working in labs actually use to diagnose HIV, HepB,

Pregnancy, hypothyroidism, etc. 9. Feedback regulation of hormone synthesis and secretion

a. peptide hormones i. synthesis

1. Gene trasncription mRNA preprohormone synthesized on ER ribosomes signal peptide cleavage in ER membrane to prohormone initial glycosylations in ER transport to trans-Golgi apparatus for further proteolytic processing/modification of


Page 139 of 168 glycosylated residues mature hormone is placed in vesicle for future secretion

ii. secretion 1. GTP binding protein attaches vesicles to specific sites within

cytoskeleton 2. calcium influx activates myosin light-chain kinase on vesicle

surface Phosphorylated myosin interacts with microfilaments creates conveyer belt made of microtubules membrane of secretory granule (vesicle) and plasma membrane fuse common membrane is lysed hormone is released into interstitium

3. usually concurrently: cAMP PKA phosphorylation of tubulin microtubules form contributes to cellular vesicle movement

apparatus facilitates pathway of vesicle release b. catecholamines

i. synthesis 1. Synthesized from tyrosine

ii. secretion 1. same as peptides (probably because they’re amino acids)

c. thyroid hormones i. synthesis & secretion

1. Tyrosine attaches to thyroglobulin (a glycoprotein) complex is exocytosed into follicular lumen at the membrane, tyrosine residues interact with I2 monoiodotyrosine (MIT) + diiodotyrosine (DIT) on thyroglobulin These complexes combine: MIT +DIT is T3, DIT+DIT is T4 (i.e., you count the iodines), either way, it’s still bound to thyroglobulin complex is endocytosed thyroglobulin is cleaved off T3 and T4 are released into blood via simple diffusion

2. Endocytotic event is stimulated by TSH d. steroid hormones

i. synthesis 1. Cholesterol Pregnenolone (rate-limiting)

a. progesterone


Page 140 of 168 i. 11-Deoxycorticosterone corticosterone

aldosterone ii. 17-Hydroxyprogesterone

1. 11 deoxycortisol cortisol 2. androstenedione testosterone

estradiol b. 17hydroxypregnenolone

i. 17hydroxyprogesterone (see above) ii. dehydroepiandrosterone androstenedione

(see above) ii. secretion

1. simple diffusion as it’s processed 2. therefore activation of synthesis is tantamount to activation of

secretion 10. understand the ubiquity of hormone control mechanisms and different levels of

cellular metabolism a. Ubiquity: Oh, we’ve got it --they’re everywhere and do everything. Just read the last

6 ½ pages and you’ll be convinced too. LOs for May 2nd: Endocrine Hormones and Mechanisms of Action – Receptors, Second Messengers and Signalling

1. Know the major classes of signal-generating hormone receptors a. Extracellular receptors aka Membrane receptors

i. Domains 1. Hormone binding domain is outside the cell 2. Active domain that will transduce the signal is inside the cell

ii. Ligands are hydrophilic iii. Actions

1. Binding event ↑or ↓ second messenger often ↑or ↓phosphorylation various effects such as vesicle release and indirect influence of transcription

iv. Categories 1. ionotropic (like ligand-gated ion channels) 2. metabotropic (like G-protein coupled receptors)

v. Action is on the level of minutes to hours 1. largely aided by second messengers exponential ↑in action

b. Intracellular receptors i. Bound to heat-shock proteins (HSPs) inside cytoplasm

ii. Binding to receptor receptor can dissociate from HSP ligand-receptor complex travels in cell binds to hormone response element (HRE) located in the promoter region of a targeted gene

1. Transcription is influenced directly 2. Multiple complexes can bind to HREs on the same gene

additive effect iii. Action is on the level of hours to days

2. Differentiate function, location and action of different hormone receptor types a. See #1.

3. Know the major types of hormone-induced second messengers involved in hormone-dependent signal transduction

a. cAMP


Page 141 of 168 i. Involved in metabolic pathways

ii. Often stimulates kinases (PKA) iii. cAMP increases calcium by opening calcium channels and allowing

extracellular calcium to enter b. cGMP

i. Involved in vasodilation c. Calcium

i. Involved in hormone and neurotransmitter release 1. calcium influx activates myosin light-chain kinase on vesicle

surface Phosphorylated myosin interacts with microfilaments creates conveyer belt made of microtubules membrane of secretory granule (vesicle) and plasma membrane fuse common membrane is lysed hormone is released into interstitium

d. Inositol 1,4,5-triphosphate or IP3 + Diacylglycerol i. Mobilizes calcium from intracellular storage and regulates cell growth

4. Classify four major types of second messenger-dependent protein kinases and their roles in signal transduction

a. PKA i. cAMP-dependent

ii. phosphorylates serine and threonine residues b. PKG

i. cGMP-dependent ii. phosphorylates serine and threonine residues

c. PKC i. Activated by calcium and phospholipids such as DAG ii. Stimulates cell division iii. Dysregulation can result in tumors iv. 12 isoforms, classified as classical, novel and atypical

d. Calmodulin-dependent protein kinase i. Activated by calcium-calmodulin complex ii. Most abundant in the nervous system iii. Involved in exocytotic release of neurotransmitters

5. Describe the mechanisms of action and general functions of receptor tyrosine kinases

a. This is a membrane-bound receptor with kinase activity i. One transmembrane domain

ii. Tyrosine is phosphorylated b. Main ligands are insulin and growth factors c. Growth factor Binds to receptor

i. Calcium influx, ii. ↑ Na+/H+ exchange,

iii. Stimulation of Phospholipase C (PLCα) d. Overexpression or overactivation hypertrophy, vascularization of hypertrophic

regions (i.e., cancer) 6. Describe the role of intracellular tyrosine kinases in signal transduction

a. JAK is an intracellular tyrosine kinase associated with a transmembrane receptor for some growth hormones

b. Growth Hormone binding events cause receptor dimerization and bind JAKs c. Bound JAKs phosphorylate JAKs and STATs d. Phosphorylated STATs dimerize translocate to the nucleus phosphorylate

transcription factors


Page 142 of 168 e. All of these phosphorylation events have taken place on the tyrosine residues of the

relevant proteins f. The cat in the hat came back, stat.

7. Compare the active and inactive states of G-proteins and identify at least four main types of effector systems activated by G-proteins

a. Heterotrimeric G-protein coupled receptors (GPCRs) i. Inactive GPCR is bound to GDP Binding event GTP replaces GDP

on GPCR GTP-bound is active α, β, γ subunits fall off of GPCR α subunit dissociates from β, γ subunits α subunit activates cAMP

ii. Meanwhile, GTP on GPCR releases one phosphate, becomes GDP α, β, γ subunits reassociate themselves with the GPCR return to constitutive inactive state

iii. Different categories of G proteins 1. Depending on the activity of the particular complex, it can be

stimulatory (Gs, αs) or inhibitory (Gi, αi) 2. GQ activates PLC cleaves phosphotidylinositol 4,5

bisphosphate IP3 + DAG a. Can activate PLA2 cleaves membrane phospholipids

releases arachodonic acid Prostoglandins, Prostocylcins, Thromboxane, and Leukotrienes Inflammation

3. GT (T for transducin) is a specialized GPCR: a. Photon Rhodopsin Activates GT cGMP

phosphodiesterase ↓cGMP closes cGMP-activated Na channels hyperpolarization

b. Monomeric GPCRs: i. Ras, Rho, Rab – monomeric G proteins, all constitutively bound to GDP

(inactive in this state) 1. Activation occurs via Guanine Nucleotide Releasing protein or

GNRP, which transfers a phosphate from free GTP to the GDP on the monomeric GPCR GTP-bound is active

2. Inactivation occurs via GTPase-activating protein (GAP), which cleaves a phosphate off, recreating the GDP constitutive, inactive status

ii. Ras and Rho are involved in linking GF receptor tyrosine kinases to their intracellular effects

8. Understand the role of G-protein mechanisms in the symptoms of cholera a. Cholera toxin catalyzes the transfer of ADP-ribose to an �s can’t bind back on

to its GPCR but it can still activate cAMP cAMP becomes constitutively stimulated Cl- channels are constitutively opened Cl- leave cell Na+ follows chloride out to maintain electric gradient water osmotically follows significant ↑in water and salt excretion (up to 20L a day of water stool) dehydration

b. rehydration is accomplished via glucose-Na+ coupled absorption water is pulled in to follow glucose even if sodium is lost

9. Compare the functional properties of two main types of protein phosphatases a. Serine-Threonine protein phosphatases

i. Protein Phosphatase I (PP1) ii. Protein Phosphatase II (PP2) – based on regulation by divalent cations

1. PP2A 2. PP2B – regulated by calcium-calmodulin. aka Calcineurin. 3. PP2C


Page 143 of 168 b. Tyrosine phosphatases – both membrane-bound (which are sometimes receptors as

well) and cytosolic 10. Know the significance of atrial natriuertic peptide receptor-coupled membrane

guanylyl cyclase and nitric oxide-depndent cytosolic guanylyl cyclase signal transduction systems

a. ANP i. ↑ blood pressure right atrium ANP activates a membrane-bound

guanylyl cyclase/NP receptor (with an ANP-binding exracellular domain, a single transmembrane domain and an intracellular guanalyl cyclase catalytic domain) ↑ intracellular cGMP activates PKG

1. vasorelaxation ↓blood pressure 2. Na+ excretion which osmotic water excretion ↓blood

volume ↓blood pressure b. NO

i. paracrine that causes vasodilation ii. NO stimulates cytosolic guanylyl cyclase cGMP PKG

vasorelaxation LOs for May 3rd: Pancreatic Hormones: Insulin, Glucagon, Somatostatin

1. Biological actions of pancreatic hormones: insulin, glucagons and somatostatin a. Insulin

i. Acts on the liver, adipose tissue, and muscle ii. ↓blood gluocse concentration:

1. inserts glucose transporter GLUT4 ↑ glucose uptake into cells 2. upregulates F2,6BPase

a. stimulates glycolysis promotes glycogen formation b. inhibits gluconeogenesis demotes glucose formation

iii. ↓fatty acid and ketoacid in blood 1. in adipose – insulin

a. fat deposition b. inhibits lipolysis

2. in the liver: ↓fatty acids ↓Acetyl CoA ↓ketoacid formation a. Insulin is THE major antiketogenic hormone

iv. ↓amino acids in the blood 1. insulin ↑ aa uptake, ↑ protein synthesis, ↓ protein degradation

(anabolic) v. ↓blood potassium concentration

1. ↑ uptake into cells b. Glucagon

i. Glucagon acts on the liver and adipose tissue ii. Second messenger is cAMP

iii. Glucagon increases blood glucose concentration 1. ↑ glycogenolysis 2. prevents recycling of glucose into glycogen 3. ↓F26BPase ↑ gluconeogenesis

iv. ↑ fatty acid and ketoacid blood concentrations 1. ↑ lipolysis

a. Beta-oxidation of fat uses NAD ↓in NAD prevents oxidation of ACoA in the TCA cycle

2. ↑ ACoA ↑ ketoacid formation


Page 144 of 168 v. ↑ urea production

1. Amino acids are used more by increased gluconeogenesis more amino acid groups are incorporated into urea ↑ urea

c. Somatostatin i. inhibits insulin, glucagon and gastrin secretion

2. Structure-function relationship between proinsulin and insulin molecules a. Proinsulin is synthesized as a single-chain peptide. Within storage granules,

proteases remove a connecting (C) peptide insulin i. C peptide is secreted along with insulin

b. 99% of proinsulin is packaged in the golgi i. 1% of proinsulin just diffuses out of the cell still gets cleaved low

level of constitutive insulin c. Insulin has A & B chains, joined by two disulfide bridges

i. A – 21 amino acids ii. B – 30 amino acids

d. Proinsulin has the additional C peptide – 33 additional amino acids 3. Synthesis, secretion & regulation of insulin

a. Synthesis – see # 2 b. Mechanism of secretion: Glucose binds to GLUT 2 on beta cells glucose is

oxidized to ATP inside beta cells K+ channels close K+ stops flowing out depolarization Calcium channels open calcium flows in vesicular fusion with the membrane is stimulated insulin secreted

i. Result is a burst of insulin followed by sustained secretion in waves (pulsatile) for about an hour following sugar consumption

c. Regulation of secretion: i. On mechanism: ↑ blood glucose concentration insulin secretion

ii. Off mechanism: Oxidation of glucose ↑ ATP has a second effect: 1. Uncoupling protein 2 (UCP-2) dissociates ATP generation from

glucose oxidation ↓ insulin secretion iii. Hypothalamic control of feeding behavior also effectively plays a role in

insulin levels iv. Drug-based regulation

1. Sulfonyl urea drugs – used in type II diabetes a. bind to SUR close K+ channels insulin release

2. Diazoxide – used in hyperinsulinemia a. opens K+ channels insulin release

4. Describe the interaction of insulin with its receptor and the significance of insulin receptor substrates (IRSs)

a. Insulin receptor is found on target tissues for insulin b. Insulin receptor has two α subunits and two β subunits c. β subunits span the cell membrane and have tyrosine kinase activity insulin binds

receptor tyrosine kinase autophosphorylates the β subunits phosphorylated receptor is activated to phosphorylate other proteins insulin-receptor complex enters target cells

i. insulin down-regulates its own receptors in target tissues 1. # of insulin receptors is ↑ in starvation and ↓in gluttony

d. IRS: i. IRS-1 and IRS-2 are expressed in muscle, adipose, pancreatic β cells

ii. IRS-3 is expressed in the brain


Page 145 of 168 iii. Insulin binding event activates IRS IRS serves as a docking station for

other protein kinases to come get activated subsequent phosphorylation events lead to all of the effects of insulin

iv. IRS 1 activates growth receptor binding protein 2 (GRB2) protooncogene RAS GTP complex mitogen-activated protein kinase (MAPK) cell growth and differentiation

5. Differentiate between the source and structure of two variant forms of glucagons a. 30-40% of plasma glucagon is of pancreatic origin

i. Preproglucagon precursor molecule Islet alpha cells glucagon b. Preproglucagon is also expressed in brain and intestine

i. Sections that are cleaved are slightly different depending on where preproglucagon is cleaved into glucagon

1. in pancreas we create glucagon 2. in other tissue we create glycentin, a slightly larger peptide

containing glucagon 6. Major stimuli and inhibitors of insulin, glucagons and somatostatin secretion

a. Insulin i. Stimuli

1. Feeding -- high blood glucose, amino acids, fatty acids a. Relationship between plasma glucose and plasma insulin is

sigmoidal: i. <50mg/dl of glucose 0 insulin secretion

ii. ½ Vmax = glucose level of 150mg/dl iii. Vmax = 300mg/dl of glucose

2. GIP 3. ACh 4. Growth hormone, cortisol 5. Glucagon

ii. Inhibitors 1. Removal of stimuli 2. Fasting 3. Somatostatin 4. NE, Epi

b. Glucagon i. Stimuli

1. Fasting – low blood glucose etc 2. High protein in the absence of carbohydrates 3. CCK 4. NE, Epi 5. ACh

ii. Inhibitors 1. Feeding – adequate or high blood glucose etc 2. Insulin 3. Somatostatin 4. Ketoacids

c. Somatostatin i. Stimuli

1. Glucose, amino acids, fatty acids, glucagon, GI hormones, β−adrenergic stimuli stimulate synthesis

ii. Inhibitors 1. Insulin, α−adrenergic stimuli inhibit synthesis


Page 146 of 168 7. Somatostatin function, secretion, effect on insulin and glucagon

a. Functions of somatostatin (released by delta cells): i. ↓glucose influx

ii. ↓amino acid influx iii. ↓growth hormone iv. ↓insulin release ↓ glucose stroage and amino acid anabolism

1. Insulin somatostatin

2. insulin glucagon v. ↓glucagon release thereby decreasing glucose production and amino acid

catabolism 1. glucagon ↑ somatostatin 2. glucagon insulin

8. Understand the physiological basis for the major symptoms of diabetes mellitus a. Insulin is either not produced or not received Glucose can’t be absorbed

Glucose is in urine, urination frequency is increased, increased loss of electroyltes b. body behaves as if it’s starving

9. Differentiate between non-insulin-dependent and insulin-dependent diabetes mellitus

Type 1 Type 2 Aka Juvenile onset, Insulin-dependent diabetes Mellitus

Aka adult onset or non-insulin diabetes mellitus

Onset by puberty Onset usually older but can be young Generally undernourished, thin patients Concurrent obesity is frequent

TNF−α may be a factor in insulin resistance 10-20% of diagnoses 80-90% of diagnoses β−cells destroyed by immune system (can originate with a viral infection), eliminated insulin production Can result from a mutation in the preproinsulin gene

Inability of β−cells to produce appropriate quantities of insulin; insulin-resistance

Ketosis is common Ketosis is rare Plasma insulin is low to absent Plasma insulin is normal to high – but not

high enough to prevent hyperglycemia Acute complication: Ketoacidosis Acute complication: Hyperosmolar

coma Unresponsive to oral hypoglycemic drugs Responsive to oral hypoglycemic drugs Treatment with insulin is always necessary Usually doesn’t require insulin

10. Understand the physiological basis of the major symptoms of diabetes mellitus a. see above questions 8 & 9

LOs for May 4th: Hormones of Pituitary glands

1. Understand the functional relationships between the hypothalamus and pituitary glands

a. Hypothalamus release hormones that stimulate the anterior pituitary gland to release its hormones

i. Hypothalamic releasing hormones are relased into the median eminence travel via blood to anterior pituitary promote secretory activities

b. Hypothalamus synthesizes hormones that are relased by the posterior pituitary gland aka neurohypophysis (therefore these are sometimes referred to as neurohormones)

2. Identify anterior and posterior pituitary hormones a. See LO Question 3 for May 1 for a thorough explanation of pathways


Page 147 of 168 b. Anterior

i. ACTH ii. TSH iii. LH iv. FSH v. GH vi. Prolactin

c. Posterior i. ADH ii. Oxytocin

3. Know the function and characteristics of ADH and oxytocin a. ADH

i. ↑ water permeability of the principal cells of LDTCD ii. ADH constricts vascular smooth muscle

b. oxytocin i. causes ejection of milk from the breast

1. stimulated by suckling, and psychological factors relating to the presence of a baby

c. ADH and Oxytocin have preprohormones which are very similar – only differing at 2 out of 9 amino acids

i. structural similarity may result in similar effects ii. cleavage of preprohormones produce neurophysins

1. preADH ADH + neurophysin 1 2. preOxytocin oxytocin + neurophysin 2

iii. Neurophysins are secreted along with ADH and Oxytocin in their vesicles iv. Absence of neurophysins vesicles can’t be transported out properly

1. actual function is unknown d. ADH

i. Stimulated by 1. ↑ plasma osmolarity 2. volume contraction of the blood 3. pain, nausea, hypoglycemia, nicotine, opiates, anti-neoplastic drugs

ii. Inhibited by 1. ↓osmolarity 2. ethanol 3. α−adrenergic agonists 4. ANP

iii. Receptors V1 and V2 1. V1A receptors vasoconstriction 2. V1B receptors ACTH secretion from ant pit Cortisol etc. 3. V2 receptors dilatory (counterbalance V1A)

a. in kidney, V2 stimulation ↑ permeability of principal cells in the LDTCD decreases diuresis

iv. Syndrome of innappropriate ADH secretion 1. Tx is to limit water & salt intake or block V1 receptors

e. Oxytocin i. Primary effect is the let-down reflex

1. Oxytocin a. myoepithelial cells contract forces milk from alveola

into ducts b. smooth muscle contraction in the uterus


Page 148 of 168 ii. Stimulators

1. suckling 2. uterine/genital stimulation

iii. Inhibited by 1. opioids

4. Differentiate between target cells of different anterior pituitary hormones and their main endocrine function

a. This was described in much more detail in the LOs for May 1st – Question 3 b. Categories of source cells:

i. Throughout chart, but somatotrophs are most common at 40-50% c. Categories of effector cells:

i. Adrenal gland – cortex ii. Adipose tissue iii. Melanocytes

Hormone Name Source Cell Target Cell Main Functions ACTH Corticotrophs Adrenal Cortex Increases steroid hormone synthesisTSH Thyrotrophs Thyroid Growth, bone formation, etc LH Gonadotrophs

Gonads Ovulation, hormone release, etc

FSH GH Somatotrophs Liver, adipose tissue Growth, lipid and carb metabolism Prolactin Mammotrophs Breasts, Gonads Lactogenesis Apparently the mnemonic is to think of a FLAT PiG in an ant pit.

5. Identify the glycoprotein hormones of the pituitary gland a. Glycoprotein hormones

i. FSH ii. LH

iii. TSH b. Each glycoprotein hormone is made of an α and β subunit – non-covalently linked

i. α subunit is common to all 3 1. single peptide chain of 92 amino acid residues with 2 carbohydrate

chains linked to its structure ii. β subunit is different in each

1. FSH and LH – 150 amino acids and 2 carbohydrate chains a. 2 different ones

2. TSH – a single peptide chain of 112 amino acid residues with 1 carbohydrate chain

iii. because these are not covalently linked, it’s more like there are just the right number of α and β subunits floating around together – neither subunit has a strong effect alone, the two must come together to have a hormonal effect

1. there’s slightly more α than β secreted and floating around 6. Explain the anterior pituitary disorders

a. Growth Hormone i. GH deficiency – Shortness. Can lead to delayed puberty, mild obesity, etc

1. can be a lack of GH or its receptor ii. GH excess – acromegaly (progressive enlargement of the hands, head, face,

feet and chest) – “Marie’s disease” 1. Giganticism


Page 149 of 168 a. occurs before puberty

2. After puberty a. bone growth, organomegaly, glucose intolerance

3. Tx with somatostatin analogs b. Prolactin

i. Deficiency failure to lactate ii. Excess

1. Caused by a. hypothalamic destruction b. prolactin-secreting tumors

2. Leads to a. galactorrhea, aka lactorrhea (milk secretions in the

absence of nursing), ↓libido b. inhibition of GnRH failure to ovulate, amenorrhea

(aka menostasis, failure of a woman to menstruate during what should be childbearing years)

3. Tx a. Bromocriptine dopamine agonist reduces prolactin

c. ACTH i. Excess: Cushing’s disease

1. Characterized by a. ↑ cortisol and androgens

i. virilization of women (women take on secondary male sexual characteristics)

ii. cortisol aldosterone hypertension iii. cortisol ↑ bone reabsorption osteoporosis

b. hyperglycemia c. ↑ protein catabolism and muscle wasting d. central obesity (round face, supraclavicular fat, fat around

the neck) e. poor wound healing f. striae atrophicae (stretch marks)

2. Tx a. Ketoconazole inhibits steroid hormone synthesis

ii. Addison’s Disease: Primary adrenocortical insufficiency 1. Caused by

a. destruction of adrenal cortex 2. causes acute adrenal crisis 3. Characterized by

a. ↓androgens, mineralocorticoids, glucocorticoids b. INCREASED ACTH because of a loss of negative

feedback c. cortical deficiency hypoglycemia d. ACTH MSH hyperpigmentation e. ↓androgens ↓pubic and axillary hair in women f. ↓aldosterone ECFV contraction, hypotension,

hyperkalemia, metabolic acidosis 4. Tx: replacing the missing cortisol and, if necessary, fludrocortisone

as replacement for the missing aldosterone iii. Secondary adrenocortical insufficiency

1. deficiency in ACTH


Page 150 of 168 a. same symptoms as Addison’s, with the following

exceptions: i. no hyperpigmentation ii. no volume contraction, hypotension,

hyperkalemia or metabolic acidosis d. Hypothalamic-pituitary dysfunction is a term to describe a nonorganic relative

inactivity of (GnRH) reduces FSH and LH 7. Understand treatment approach to anterior pituitary diseases

a. See throughout answer to #6 8. Explain regulation of luteinizing hormone secretion

a. LHRH i. LHRH is essential for gonadotrophin secretion gonadal hormone

regulation of LH and FSH ii. LHRH release is pulsatile – frequency is important in regulating LH and

FSH differentially 1. more frequent more LH 2. less frequent more FSH

b. Feedback effects of gonadal steroids and peptide hormones (inhibin) i. LH upregulates itself midcycle (see LOs for May 1)

1. LH interacts with membrane receptors regulates LH and FSH synthesis and release – essential for normal gonadotroph function

c. Calicum/IP3/DAG 2nd messenger cascade

d. Estradiol, dihydrotestosterone suppresses frequency of LHRH secretion 9. Know the significance of hormone replacement therapy

a. Hormone replacement therapy (HRT) is a system of medical treatment for perimenopausal and postmenopausal women, based on the assumption that it may prevent discomfort and health problems caused by diminished circulating estrogen hormones. The treatment involves a series of drugs designed to artificially boost hormone levels. The main types of hormones involved are estrogens, progesterone or progestins, and sometimes testosterone. We covered this more in biochem.

LOs for May 5th: Growth hormone

1. Describe the regulation of growth hormone (GH) synthesis and secretion a. GH is a single large polypeptide of 191 amino acids, in a helical conformation, with

two disulfide bridges b. GH stimulates DNA, RNA and protein synthesis c. Hypothalamus GHRH Ant pit GH [Hypothalamus Somatostatin]

[Ant Pit GH] i. GHRH release from the hypothalamus is upregulated by sleep, stress &

dietary amino acids ii. GHRP also acts on the hypothalamus and the ant pit

iii. somatostatin is aka somatotropin releasing inhibiting factor (SRIF) d. GH IGF (aka somatomedin)

i. IGF makes you grow, ↑ protein synthesis in muscle ↑in lean body mass, ↑ organ size

ii. IGF [Ant Pit GH] iii. IGF ↓cAMP and calcium levels in the Hypothalamus somatostatin

[Ant Pit GH] iv. IGF GHRH


Page 151 of 168 e. Second messengers:

i. GHRH binds to a receptor on anterior pituitary 1. Adenylyl cyclase into cAMP

a. Calcium rushes in from outside b. PKA

2. Phospholipase C/Diacylglycerol / IP3 pathway Calcium is released from intracellular stores in the ER activates PKC

2. Know the mechanisms through which GH release is controlled a. See answer to question 1 b. Upregulation

i. long-term GHRH ↑ GH transcription, activated by Pit-1 transcription factor

ii. Thyroid hormone, cortisol synergistically enhance transcription of GH iii. Estrogen, testosterone mildly enhance transcription of GH

3. Discuss GH concentrations and factors that affect release into circulation a. GH is detectable in fetal serum and increases rapidly to reach a peak of 100-150μg/l

at the 20th week of gestation b. Mean halflife of exogenously administered GH ranges from 9-27 minutes

(physiologically) Figure 43-20 Lifetime pattern of GH secretion. GH levels are higher in children than in adults, with a peak period during puberty. GH secretion declines with aging. Premature babies have higher levels of GH at birth than do babies carried to full term, but the levels drop over the first few months of life before increasing as shown in this graph. The clear decrease in GH during senescence may play a role in aging. This graph represents a normal pattern of GH secretion, but levels can be altered by nutrition, sleep, stress and exercise. During childbearing years, women have more GH than men.

4. Explain the effect of somatostatin on GH release a. 14 or 28 amino acid peptide released from hypothalamus b. potent inhibitor of GH release c. GHRH noncompetitively (has its own receptor)

i. ↓intracellular calcium and cAMP 5. Relationship between GH actions and peripherally generated peptide mediators

a. Peripherally generated peptide mediators are IGFs b. JAK-STAT pathway controls IGF expression

i. GH binds to a 1-transmembrane receptor receptors dimerize JAKs are docked and activated autophosphorylate and then phosphorylate STATs

6. Relationship between insulin-like growth factors (IGFs) and GH actions on growth a. GH IGFs

i. Circulating IGFs originate in the liver circulate bound to large binding proteins, which regulate their availability to tissues

1. GH stimulates production of these binding proteins 2. All IGFs (especially IGF-1) are reduced in individuals with reduced

GH


Page 152 of 168 ii. Example: GH directly stimulates pre-chondrocyte differentiation

chondrocytes release IGF clonal expansion and maturation of chondrocytes collagen and proteoglycan chondroitin production are stimulated in chondrocytes

iii. Cortisol, estrogens, and other antagonists of GH all IGFs b. Different IGFs:

i. IGF-2 (and its receptor) are expressed early in fetal development; ii. IGF-1

1. is correlated with pubertal growth 2. enhance longitudinal growth

a. longitudinal: running in the direction of the long axis of the body, i.e., verticle unless you’re really the wrong shape

c. Pathology i. Fasting – ↑ GH but ↓IGF

1. if you lose your [GH IGF], you make more GH in vain 2. a dietary element mediates the relationship between GH and IGF

ii. GH deficiency 1. Defect in GH or IGF will each cause diminished growth 2. Tx give IGF plasma amino acid levels go down

a. all tissues respond, long bone growth is most significantly increased

b. lean body mass ↑ c. fat mass decreases d. resting metabolic rate, exercise capacity, general sense of

well-being all increase e. tall people are happier than short people f. sorry, Whitney

7. Relationship between IGFs and anabolic processes a. See Answer to #6

8. GH opposition to insulin action a. GH stimulates expression of insulin, but also induces resistance to insulin:

i. GH insulin transcription ii. GH glucose uptake plasma glucose concentration rises

1. prevents hypoglycemia during fasting iii. GH enhances lipolysis iv. GH insulin-stimulated lipogenesis plasma fatty acid level rises,

adipose tissue decreases 1. In this way GH is diabetogenic

9. Clinical manifestation of acromegaly a. progressive enlargement of the hands, head, face, feet and chest) – “Marie’s disease” b. Caused by:

i. pituitary tumor ii. hyperpituitarism iii. excessive GH secretion

10. GH deficiency and replacement therapy in children a. Children without GH are short, are delayed in skeletal and sexual maturation b. Dx

i. GH levels don’t rise after administration of GH stimulator ii. Non-responsiveness to T4 thyroid hormone (thanks, Hurley)

c. Tx


Page 153 of 168 i. Give GH

1. enhanced positive nitrogen balance 2. ↓urea production 3. redistributes fat 4. reduces carbohydrate utlization

a. no increase in diabetes incidence 5. A dose will have these effects for a few hours only

LOs for May 8th: Thyroid Hormone

1. Understand the synthetic process of thyroid hormones and importance of dietary iodide in this process

a. synthesis & secretion: Because this reaction changes sides of the cellular membrane, I have underlined portions that take place inside the cell and italicized portions that take place outside the cell. Traversions have been left in unaltered font.

i. Iodide is imported into the cell via Na+/I- symporter Tyrosine attaches to thyroglobulin (a glycoprotein) complex is exocytosed into follicular lumen at the membrane, tyrosine residues interact with I2 monoiodotyrosine (MIT) + diiodotyrosine (DIT) on thyroglobulin These complexes combine: MIT +DIT is T3, DIT+DIT is T4 (i.e., you count the iodines), either way, it’s still bound to thyroglobulin complex is endocytosed thyroglobulin is cleaved off T3 and T4 are released into blood via simple diffusion

1. MITs and DITs that failed to combine are deiodinated so that the components (especially I2) can be recycled

ii. Endocytotic event is stimulated by TSH iii. T4 is converted into T3 or rT3 in tissues

1. Enzyme is: 5-monodeiodinase 2. T3, triiodothyrodine, is more biologically active than T4 3. rT3 is inactive (reverse T3) 4. T4 is tetraiodothyrodine or thyroxin 5. T4/T3 ratio is 10/1 (T3 is more biologically active, so you don’t

need as much of it) iv. Hypothalamus TRH Ant Pit TSH Thyroid T3, T4

1. Ant Pit 2. Hypothalamus

2. Discuss the regulation of thyroid hormone synthesis and secretion by the hypothalamic-anterior pituiary axis

a. Endogenous i. T3 TSH release, gene expression, and receptors

ii. Dopamine, somatostatin, cortisol, GH TSH secretion b. Environmental

i. Insufficient dietary iodide not enough I2 to make MIT and DIT 3. Steps in thyroid hormone synthesis both intracelluarly and outside the cell (inside

the colloidal space) a. See Question 1 b. Active iodide uptake –

i. at basal membrane of thyrocyte by Na+/I- symporter 1. Na/K ATPase powers

ii. Normal thyroidal Iodide uptake is 150μg/day c. Thyroid peroxidase


Page 154 of 168 i. Converts I- to I2

ii. I2 can covalently bind to tyrosines of thyroglobulin iii. Requires hydrogen peroxide

4. Reciprocal negative feedback of thyroid hormone on its synthesis and secretion a. See Question 1 and 2

5. Importance of serum binding proteins on the metabolism and availability of free hormone and its degradation/excretion

a. T4 and T3 circulate bound to thyroxine binding globulin (TBG), a hepatic glycoprotein

i. binding is 1:1 ii. 20% of THs are bound to TBG

1. TBG concentration varies a. can disturb ratio of free to bound T4 b. acute hepatic disease, pregnancy, estrogen therapy,

kidney disease iii. 80% of THs are bound to transthyretin (thyroxine-binding pre-albumin) or

albumin iv. .03% of T4 and .3% of T3 are in the free state

1. T3 has lower affinity for binding proteins, producing the differential binding patterns, and explaining the differential biological activity

v. The best things in life are free b. Degradation/excretion

i. Thyroid hormone is metabolized by deiodination, deamination, and conjugation with glucoronic acid

1. the conjugate is secreted via the bile duct into the intestine 2. normally, T3 and T4 are excreted in the feces

6. Primary physiological effects of thyroid hormone and its effects on general metabolic processes

a. Thyroid hormone increases i. basal metabolic rate

1. more rapid drug metabolism 2. vitamin turnover 3. steroid hormone metabolism

ii. thermogenesis 1. moderated by blood flow, sweating and ventilation

iii. Na/K ATPase ↑ ADP ↑ oxygen need 1. T3 adenine nucleotide translocase (a mitochondrial membrane

enzyme) activation brings ADP into mitochondria and pushes ATP out of mitochondria faster

iv. oxygen consumption 1. 150ml/min in hypothyroidism 2. 250ml/min in euthyroidism 3. 400ml/min in hyperthyroidism

v. renal effects 1. kidney size ↑ 2. ↑ RPF, GFR 3. ↑ reabsorption

vi. cardiac effects 1. ↑ SV 2. ↑ sarcolemmal uptake of calcium shortens diastole ↑ HR 3. ↑ systolic pressure


Page 155 of 168 4. ↓diastolic pressure

vii. development 1. normal fetal development 2. brain development 3. cartilage ossification 4. linear growth of bone 5. maturation/activity of chondrocytes 6. normal lactation

7. Iodide metabolism and intrinsic component of thyroid hormone synthesis a. Addressed in question 2

8. Mechanisms of thyroid gland activity and its regulation a. Addressed throughout

9. Thyroid hormone receptors and intracellular signals a. Hypothalamus TRH receptor is on anterior pituitary ↑ IP3 ↑ Ca

TSH release receptor on thyroid ↑ cAMP ↑ Ca i. ↑ iodide trapping ii. coupling of MIT and DIT iii. Endocytosis of colloidal Thyroglobulin-TH iv. Proteolysis of thyroglobulin (cleavage)

b. TRH TRH receptors 10. Effects of excess or deficiencies of thyroid hormone and the consequences of

hyperthyroidism and replacement therapy a. Excesses

i. Symptoms of hyperthyroidism: an increase in metabolic rate 1. weight loss, ↑ food intake 2. excessive thermogenesis, sweating, thirst, ventilation 3. muscle weakness and atrophy, and osteoporosis (because of

protein breakdown) 4. ↑ HR and CO 5. Emotional lability -- irritable and hyperexcitable

a. what’s wrong with that? ii. Causes: Proximal cause of symptoms is increase in T4 and/or T3 levels,

due to a variety of pathological conditions. 1. Graves disease

a. autoimmune b. antibody binds to TSH receptor agonizes

overactivates TSH too much THs 2. thyroid neoplasm

a. TSH-producing tumor 3. inflammation of the thyroid 4. excess TSH 5. Dietary excess of T3, T4 or iodine

a. What? You’ve never eaten thyroid? Where have you been? 6. Overdose of therapeutic THs

iii. Tx 1. β−adrenergic antagonists 2. Thiouracil blocks synthesis of TH 3. Surgical or radioactive ablation of thyroid tissue

iv. Thyrotoxic crisis 1. When thyrotoxicosis causes acutely increased metabolism, it is

sometimes called "thyroid storm" and is life-threatening


Page 156 of 168 b. Deficiencies

i. Symptoms of hypothyroidism 1. Perinatal

a. retarded growth (longitudinal and developmental) b. marked ↓in myleination and arborization of neurons in the

brain Cretinism 2. Adulthood

a. listlessness, sloth, somnolence, slowed speech, impaired memory, decreased mental capacity, intolerance to cold, decreased perspiration, dry skin, low CO, weight gain

ii. Causes 1. Surgical thyroid removal 2. Too much treatment for hyperthyroidism 3. Congenital cretinism 4. Idiopathic decreased TRH or TSH 5. Hashimoto's thyroiditis, the most common form of thyroiditis, is

an autoimmune disease where the body's own antibodies fight the cells of the thyroid. It is more prevalent (8:1) in women than in men, and its incidence increases with age. The genes implicated vary in different ethnic groups and the incidence is increased in patients with chromosomal disorders, including Turner's, Down, and Klinefelter's syndromes. Hashimoto's thyroiditis usually results in hypothyroidism, although in its acute phase, it can cause a transient hyperthyroid state. Treatment is with daily thyroxine, with the sodium salt of thyroxine liothyronine given when the need to raise levels of circulating thyroxine is urgent.

iii. Tx 1. TH replacement such as thyroxine (sold as Synthroid)

LOs for May 9th: Adrenal Cortex Hormones Note: Somehow the most basic information was not contained in these questions, so before reading them: 1. The adrenal cortex hormones are cortisol (aka hydrocortisone, a glucocorticoid), aldosterone (a mineralocortocoid) and the androgen precursors (especially dehydroepiandrosterone sulfate or DHEA-S,which ultimately becomes both testosterone and estradiol) 2. The three zones of the adrenal cortex are (from out to in): The zonula glomerulosa – which secretes aldosterone (“salt”) The zonula fasciculata – which secretes cortisol (“sugar”) The zonula reticularis – which secretes preandrogens (“sex”) (Remember? Salt – sugar- sex – the deeper you go, the better it gets). Ok. On to the LOs.

1. Regulation of adrenocortical function by hypothalamic-pituitary-adrenal axis a. Hypothalamus CRH Ant Pit ACTH

i. Adrenal gland cortisol 1. [Ant Pit ACTH] 2. [Hypothalamus CRH]

ii. [Hypothalamus CRH] iii. aldosterone (slightly)

b. ↑K+ and ↓ ECFV Aldosterone secretion


Page 157 of 168 c. ↓Na+, ↓ECFV, ↓BP, ↓RBF JG cells Renin Angiotensin II adrenal

cortex aldosterone secretion 2. General biochemical pathway for the synthesis of adrenal steroid hormones

a. synthesis i. Cholesterol Pregnenolone (rate-limiting)

1. progesterone a. via 21 hydroxylase 11-Deoxycorticosterone via 11

hydroxylase corticosterone via aldosterone synthase aldosterone or [18- hydroxycorticosterone

aldosterone] i. The ability of 18-hydroxycorticosterone to convert

to aldosterone is critical b. 17-Hydroxyprogesterone

i. 11 deoxycortisol cortisol 1. 11 deoxycortisol is hydroxylated in the 11

position by 11−β−hydroxylase. This is the critical final step in synthesis of cortisol.

ii. androstenedione testosterone estradiol 2. 17-hydroxypregnenolone

a. 17hydroxyprogesterone (see above) b. dehydroepiandrosterone (DHEA) androstenedione

(see above) ii. Note: 11 deoxycorticosterone and 18 hydroxycorticosterone, although they

are also intermediates, are active mineralocorticoids. Corticsterone can exhibit cortisol-like functions in the absence of corticol.

3. Regulatory mechanisms of aldosterone and cortisol synthesis and secretion a. See questions 1 and 2 b. ACTH

i. Rapid inhibition: 1. Cortisol blocks CRH

ii. Slow inhibition: 1. Cortisol blocks gene transcription

c. Secretion is via simple diffusion – no storage takes place, therefore processing must be expedient

4. Pathways of hormone production in adrenal cortex, and whether deficiency of one enzyme can lead to overproduction of a different hormone

a. See above answers (esp #1) b. If you can’t synthesize cortisol, you can use corticosterone (an aldosterone

precursor) instead 5. Mechanisms of actions of cortisol and aldosterone, and how hormone receptor

binding causes the physiological response a. Cortisol

i. essential for maintenance of plasma glucose and survival during fasting ii. facilitates many physiological processes, including

1. metabolic processes a. sustained glucose production from protein and reduces

sensitivity to insulin (strongly antagonistic) i. diabetogenic

b. anabolic functions: i. hepatic glucose production – gluconeogenesis


Page 158 of 168 1. ↑ serum glucose

ii. hepatic glycogen production iii. prevent hypoglycemia during fasting iv. stimulates mobilization of amino acids and their

conversion to glucose c. catabolic functions

i. breaks down muscular glycogen, protein and lipid 2. vascular responsiveness and muscle function 3. skeletal turnover 4. CNS modulation 5. hematopoeisis 6. renal function 7. immune responses

iii. ACTH binds to fasciculata cell cAMP 1. Immediate response:

a. steroidogenesis b. ↑ cholesterol esterase c. ↓cholesterol ester synthetase d. ↑ cholesterol transport into mitochondria e. ↑ cholesterol binding to P450 – the enzyme that catalyzes

[cholesterol pregnenolone] 2. Subsequent response:

a. ↑ transcription of P450 b. ↑ transcription of adrenoxine

i. is required along with NADPH for conversion of cholesterol to the active hormones

c. ↑ transcription of LDL receptor i. important for initial absorption of cholesterol

3. Longterm response: a. ↑ size and number of adrenocortical cells

b. Aldosterone i. sustains ECFV by conserving Na+

ii. prevents K+ overload by accelerating its secretion iii. Angiotensin II activates type 1 receptors in glomerulosa cells IP3/Ca

aldosterone synthesis & release iv. Stimulating factors (despite what Pandey wrote)

1. hypovolemia low RPF renin 2. acute diarrhesis 3. sodium deprivation

v. Inhibiting factors 1. excess sodium intake 2. hypervolemia

6. Action of aldosterone on kidney function and blood pressure regulation a. reduced ECF reduced RBF ↓JG stretch renin [Angiotensinogen

Angiotensin I] [via ACE] Angiotensin II activates Type 1 receptors in adrenal glomerulosa cells IP3/Ca

i. PKC aldosterone synthesis aldosterone is lipid and therefore is released via diffusion

1. K+ secretion 2. Na+ reabsorption water reabsorption rectifies low ECF

ii. ↑ K+ ↑ aldosterone release


Page 159 of 168 1. Explanation taken from

www.uhmc.sunysb.edu/internalmed/nephro/webpages/Part_D.htm "Aldosterone stimulates distal nephron secretion of potassium. The stimulation of secretion is related to the ability of aldosterone to stimulate sodium potassium ATPase activity in cells of the distal tubule as well as its ability to alter the apical (urinary) membrane conductance of potassium in these cells. In the absence of aldosterone, body potassium content and plasma K+ are increased due to a decrease in renal excretion of potassium. In the presence of excess aldosterone both total body K+ and plasma K+ are decreased. An increased plasma K+ stimulates aldosterone secretion and decreased plasma K+ suppressed it."

7. Discuss the clinical impications of cortisol in patients with serious illnesses a. Excess cortisol can occur in sepsis, fractures, surgery, or hypoglycemia

i. levels can be 2-5 fold higher than normal ↑ risk of fatality b. Sx of excess steroids

i. Muscle weakness and atrophy ii. osteoporosis

iii. inhibition of tissues’ ability to eliminate noxious substances and invaders iv. delays normal wound healing v. ↑ susceptibility to infection

c. Tx use of cortisol i. in acute inflammatory reactions

ii. should not be used during infection, diabetes and osteoporosis d. See LOs for May 4th – there is a whole section on Addison’s and Cushing’s

8. Understand the role of glucocorticoids in reaction to stress, injury and fasting a. Stress – triggers cortisol release, can override negative feedback mechanisms

therefore triggers cortisol release even in the overabundance of cortisol i. prolonged exercise and other forms of severe pain promote cortisol release ii. endorphic analgesia blocks cortisol release

b. Injury – cortisols are anti-inflammatory because they protect vesicles containing proinflammatory proteins from being exocytosed

c. Fasting – see question 5 9. Clinical implications of aldosterone and its role in sodium, potassium, and water

balance a. Aldosterone increases sodium and water retention and potassium secretion b. See question 5

10. Significance and effect of atrial natriuretic peptide hormone on aldosterone secretion a. ANP inhibits aldosterone release (strong effect) b. ↑ blood pressure right atrium ANP Na+ excretion osmotic water

excretion ↓blood volume ↓blood pressure c. ANP inhibits aldosterone release prevents sodium and water reabsorption

prevents increase of ECFV 11. No LO, but if you’re interested in androgens…

a. adrenal androgens undergo peripheral conversion to testosterone and estrogen: adrostene dione estrone and testosterone

i. in males, the amount of testosterone produced via this pathway is generally insignificant in comparison to testicular testosterone

ii. in postmenopausal women, this is an important source of estrogens


Page 160 of 168 iii. in fetal adrenal glands 16-α-hydroxylase is active and converts DHEA-S to

16-hydroxy-DHEA-S converted via desulfation and aromatization estriol

1. estriol can increase up to 1000-fold during pregnancy a. biomarker of fetal wellbeing and placental adequacy

b. adrogential syndrome i. caused by androgen-secreting tumors or by lack of negative feedback on

ACTH production c. insufficiencies can be caused by

i. autoimmune deficiency ii. congenital enzyme deficiency

LOs for May 10th & 11th: Calcium Homeostasis

1. Distribution and metabolism of calcium in the body a. Distribution

i. 99% in bones – 1 kg 1. Of this, all is theoretically exchangable but only .4% (or 4g) is

rapidly exchangable – labile or young bone, which is considered to be in physiochemical equilibrium with the ECF

2. Of this, generally 500 mg calcium per day is deposited to bone and reabsorbed from bone – so net bone mass stays constant during this exchange

ii. 1% plasma calcium 1. Locations

a. 1300 mg ECF b. 13,000 mg ICF

2. Types a. ½ total diffusable

i. 90% ionized free calcium – biologically active, second-messenger calcium

ii. 10% - complexed to bicarb, citrate, other small anions

b. ½ total non-diffusable – bound to proteins, mostly albumin

b. Metabolism i. Recommended daily consumption 1000 mg

1. 350 mg absorbed 2. 250 mg secreted 3. 900 mg excreted (1000-350+250=900)

ii. Positive balance – seen in children when excess calcium is absorbed in comparison to that excreted

iii. Negative balance – seen in women during pregnancy and during postpartum lactation, when intestinal absorption of calcium is less than calcium excretion

2. Physiological importance of plasma ionized free calcium levels a. Plasma concentration of total calcium (ionized and non-ionized) is 10mg/dL or

2.5mM/L or 5 mEq/L i. Biologically active aka ionized, free calcium is about 1.1mM/L

b. Calcium homeostasis is critical for i. neuronal excitability


Page 161 of 168 1. decreased calcium hyperexcitability 2. increased calcium sloth

ii. neurotransmitter release iii. membrane integrity iv. muscular excitation-contraction coupling

1. calcium binds to specific binding proteins (calmodulin in non-muscle and smooth muscle cells, and troponin C in skeletal muscle)

v. endocrine secretion vi. coagulation

c. Hypocalcemia i. Signs and symptoms

1. CNS a. Excitation thresholds decreased

i. Calcium competes with sodium in the sodium channels lower calcium less inhibition Na+ permeability is increased raising resting potential easier to meet threshold

b. CNS dysfunction – confusion to seizures c. paresthesia in extremities d. muscular cramps e. muscular spasm tetany

i. laryngospasm is life-threatening 2. CV

a. delayed repolarization b. long QT

3. Chronic paradoxical deposition of calcium a. in basal ganglia b. cataracts

4. Chvostek’s sign (pronounced Swastika) a. Tapping on facial nerve at the angle of the mandible

produces ipsilateral facial muscle contraction 5. Trousseau’s sign

a. Hand spasm b. can be triggered in a hypocalcemic person by inflating a

blood pressure cuff around the arm ii. Etiology

1. malabsorption 2. inadequate dietary intake 3. hypoparathyroidism – often caused by thyroid surgery 4. renal disease 5. vitamin D deficiency

d. Hypercalcemia i. Signs and symptoms

1. CNS a. Excitation thresholds increased b. lethargy c. depression d. psychosis e. coma f. neuromuscular weakness

2. CV a. hypertension


Page 162 of 168 b. bradycardia

3. Renal a. *most common complaint b. nephrocalcinosis (kidney stones) c. reduced GFR d. polyuria e. dehydration

4. GI a. nausea b. vomiting c. constipation d. anorexia e. pancreatitis

ii. etiology 1. primary hyperparathyroidism 2. vitamin D intoxication 3. secondary hyperthyroidism 4. malignancies:

a. release of PTH-related proteins b. cytokines or prostaglandins c. osteolytic bone metastases

3. Relationship of total plasma calcium levels and ionized free calcium levels – and the effects of changes in blood pH

a. normally, 50% of calcium is bound to plasma proteins b. acidosis and temporary hypercalcemia:

i. acidosis decrease in pH more H+ = more positive ions in the body plasma proteins becomes less negative calcium is less attracted to

plasma proteins the rate of divorce increases more free calcium is found in the serum <50% of calcium will be bound (hypercalcemia)

body will try to compensate by depositing more calcium into bone and secretion total bound+unbound calcium in the blood isreduced normalize

c. alkalosis and temporary hypocalcemia: i. alkalosis increase in pH less H+ = fewer positive ions in the body

plasma proteins becomes more negative calcium is more attracted to plasma proteins more couples stay together less free calcium is found in the serum >50% of calcium will be bound (hypocalcemia) body will try to compensate by absorbing more calcium into blood from bone and from GI tract total bound+unbound calcium in the blood is increased normalize

d. These changes in calcium binding occur very rapidly in response to pH changes e. During pregnancy:

i. ↑ protein synthesis ↓ plasma ionized calcium ↑PTH normalizes plasma ionized calcium total Ca2+ levels are high but plasma Ca2+ levels are normal so if you do an overall assay for calcium, hypercalcemia may be found but it’s not accurate

4. Production, effects and regulation of parathyroid hormone a. Production

i. Parathyroid chief cells PTH ii. Synthesized as preproPTH in ER, pre cleaved off proPTH in

golgi, pro cleaved off PTH secreted via granules


Page 163 of 168 iii. PTH has 84 amino acids, only 34 are biologically active

1. synthetic PTH is 34 amino acids b. Receptors

i. Found on kidney, bone, intestinal membranes ii. Three types:

1. CPTH a. binds to c-terminus of PTH

2. hPTH2 a. h for human b. no, seriously c. main receptor for PTH binding d. ↑cAMP ↑ calcium permeability mediates renal

effects 3. hPTH/PTHrP

a. binds both PTH and PTHrP i. PTHrP its akin to PTH, mostly paracrine action, is

mostly in utero and for cartilage development b. PTH binds ↑cAMP c. PTHrP binds ↑PLC IP3/DAG ↑Ca2+ ↑PKC

c. Effects i. Increases reabsorption of calcium from bone into plasma

1. Side effect: releases phosphate from bone decrease reabsorption in renal tubules excrete phosphate in urine decrease plasma phosphate concentration overall, phosphate is lost from the bone, but levels are maintained in the plasma

ii. Increase renal calcium reabsorption iii. PTH is needed to make Vit D into its active metabolites (which are

necessary for calcium reabsorption) iv. In the bone:

1. PTH stimulates osteoblasts and osteoclasts net effect depends on level of PTH

a. low levels build bone b. high levels degrade bone

d. Regulation i. Low serum calcium or magnesium ↑PTH ii. Severe decreases in magnesium inhibit PTH hypoparathyroidism

hypocalcemia iii. ↑ phosphate levels ↑ PTH iv. Calcium Calcium-sensitive receptors on chief cells of parathyroid gland

IP3 turnover PTH 1. ↓ conversion of Vitamin D to calcitriol 2. ↑ conversion of Vitamin D to 24,25 dihydroxycholecalciferol

a. Note: At normal plasma calcium level, we have 50% PTH secretion

v. Active Vitamin D metabolite 1,25-dihydroxycholecalciferol ↓preproPTH mRNA

e. Degradation i. in the liver by Kupffer cells fragments cleared by kidney

1. fragments can be found by assays a. Old assays found all fragments overestimate


Page 164 of 168 b. New assays use two antibodies to identify only the number

of active segments – “Intact PTH ELISA” or “Sandwich” i. That’s right. Yum.

f. Pathology i. Pseudohypoparathyroidism:

1. Hypoparathyroidism with normal or high circulating PTH 2. pathology is in the receptors

a. More common: ↓GPCR activity ↓cAMP b. Less common cAMP normal, problem is in phosphate

clearance in the kidney 3. Sx

a. Hypocalcemia b. Hyperphosphatemia (can’t excrete phosphate)

ii. Parathyroidectomy 1. Sometimes some or all of the parathyroid glands are removed

during a thyroidectomy, though obviously never by a surgeon trained at Tulane.

2. Hypocalcemia, hyperphosphatemia 3. Symptoms develop 2-3 days after surgery – including tetany and

potential for laryngospasm (fatal) 4. Tx

a. Short term: Calcium b. Long term: PTH replacement

iii. Hyperparathyroidism 1. Caused by PTH-producing tumor 2. Sx

a. hypercalcemia calcium kidney stones b. hypophosphatemia

3. Usually asymptomatic iv. Secondary hyperparathyroidism

1. increased PTH excretion due to chronically low plasma Ca2+ 2. common in renal disease – because kidneys activate vitamin D, so

a. Renal failure ↓ kidney mass ↓1-α-hydroxylase no active vitamin D can’t absorb Ca2+

i. Vitamin D supplements won’t help v. Hypercalcemia of malignancy

1. Complication of cancer 2. Two types

a. 80% PTHrP secreted by tumors b. 20% bone-eroding metastases

5. Production, effects and regulation of dihydroxycholecalciferol a. Production

i. Vitamin D is synthesized in the skin under UVB light 1. 7-dehydrocholesterol via sunlight previtamin D3

ii. Vitamin D is a secosteroid, which means a steroid with open B ring (we do not need to recognize the structure)

iii. Vitamin D3, aka cholecalciferol, has to be converted to 1,25 dihydroxycholecalciferol to be active:

1. Taken to the liver by vitamin D3 binding protein (DBP to friends) 2. In the liver: Cholecalciferol via 25-hydroxylase 25-

hydroxycholecalciferol in the proximal renal tubules:


Page 165 of 168 a. via 1α-hydroxylase 1,25-dihydroxycholecalciferol

(active) – aka 1,25-(OH)2-D3 or calcitriol b. via 24-hydroxylase 24,25-dihydroxycholecalciferol

(inactive) 3. low serum calcium, increased PTH, low serum phosphate all

increase 1α-hydroxylase activity b. Effects/Mechanism of action

i. Calcitriol aka active Vitamin D aka 1,25-(OH)2-D3 binds to an intracellular receptor exposes DNA-binding region on receptor ↑Calbindin-D proteins bind calcium ↑ Calcium absorption

ii. Increases levels of two different calbindins iii. 1,25-(OH)2-D3 ↑ production of Ca2+/H+ ATPase ↑ Calcium

absorption 1. Favored in the presence of PTH

iv. 1,25-(OH)2-D3 increases PO4 and Ca2+ absorption in intestine and kidney v. 1,25-(OH)2-D3 increases osteoblast synthetic activity and also promotes

degradation overall, it increases bone turnover, but the exact mechanism is not understood

c. Regulation i. 1-�hydroxylase converts 25-(OH)-D3 to1,25-(OH)2-D3

ii. PTH ↑1-αhydroxylase

iii. Calcium PTH iv. Phosphate 1-αhydroxylase

v. 1,25-(OH)2-D3 1-αhydroxylase and PTH vi. 1,25-(OH)2-D3 ↑24-hydroxylase

d. Pathology i. Deficiency rickets in children, osteomalacia in adults (very rare in adults

in developed countries) 1. Sx

a. weakness b. bowing of weight-bearing bones c. dental defects d. hypocalcemia

2. Tx a. Vit D

i. effective in most cases, though Vitamin-D resistant osteomalacia is possible

3. Difference between osteomalacia and osteoporosis: a. In osteomalacia: Defect in mineralization of osteoid – lack

of incorporation of calcium or phosphate into bone matrix i. effects appendicular skeleton

ii. may involve generalized myopathy and bone tenderness (can be severe)

b. In osteoporosis: Quantity of normally mineralized bone is reduced

i. predominantly effects axial skeleton ii. no Sx until first fracture

c. Thanks to the University of Washington school of medicine for this information.


Page 166 of 168 ii. Deficiency from lack of sun exposure is more common in people of

African-American descent, migrants exposed to less light than they were previously, pregnant women, and in people living in sunless, cold, heartless, places

1. It’s a good thing they have lots of cows and cheese up in Wisconsin

iii. Deficiency is mainly due to decreased plasma calcium and phosphate 6. Production, effects and regulation of calcitonin

a. Production i. Parafollicular cells (of thyroid) Calcitonin

b. Effects i. Calcitonin inhibits bone reabsorption by directly inhibiting osteoclasts

decreases calcium serum levels ii. Calcitonin decreases calcium reabsorption in the kidney decreases

calcium serum levels iii. Treats hypercalcemia, has other hypothesized protective roles

1. may protect against post-feeding hypercalcemia 2. may be important for bone development

iv. No symptoms are associated with dysregulation of calcitonin c. Regulation

i. Increased serum calcium stimulates calcitonin release ii. Plasma levels of calcium <9.5mg/dL no secretion of calcitonin

iii. Plasma levels of calcium >9.5mg/dL linear increase of calcitonin 1. Normal plasma calcium is 5 mg/dL

iv. β-adrenergic agonists, dopamine, estrogens, gastrin, secretin, CCK, glucagon all lead to increased calcitonin secretion


Page 167 of 168

7. Causes, signs & symptoms, and treatment options of osteoporosis

a. Etiology i. caused by relative excess of osteoclastic fucntion (sic)

b. Sx/Signs: i. loss of bone matrix increased incidence of fractures in the absence of

trauma ii. Trabecular bone is lost more rapidly because it has higher metabolic rate

1. trabecular bone is primarily in the bone in the heads of the bones, not in the shafts, and it is this bone closer to joints that is most at risk of fracture due to osteoporosis

2. most commonly seen in forearm, hip and in vertebral bodies – all areas rich in trabecular bone

c. Most common form of osteoporosis is involutional (age-related) – i. Women are at higher risk due to lower peak bone mass

ii. Postmenopausal estrogen drop decreases bone mass further d. Bone fracture risks

i. Aging, menopause, other risk factors increased bone loss low bone density fractures

ii. Men have a higher peak, in 20s and 30s than women (phase 1), men and women have similar bone loss with age (phase 3) but women have an additional phase (2) during which we have menopausal bone loss

iii. Low Peak bone mass low bone density fractures iv. Propensity to fall, poor bone quality fractures v. Prolonged bed rest accelerated bone reabsorption and hypercalcemia

(reversible) e. Tx


Page 168 of 168 i. Increased dietary calcium/Vit D ii. Increased exercise iii. Estrogens (many side effects make this a non-ideal Tx)

1. Side effects: Increased risk of cancer and CV disease 2. Raloxifene (Evista) is the only SERM we’ve learned about that is

indicated for osteoporosis because it doesn’t cause cancer, and according to JAMA 2002, it may even protect against CV disease in women with propensity for CV problems

iv. Drugs 1. Bisphosphonates osteoclasts

a. Fosemax, Boniva 2. Calcitonin (injection or nasal spray)

a. Salmon calcitonin is the calcitonin of choice because its 20 times as effective as human calcitonin (works even better with Stefan’s dill sauce).

3. PTH – low injected doses anabolic a. Forteo

f. Other hormones affecting calcium metabolism (and therefore osteoporosis) i. Glucocorticoids

1. short term osteoclasts ↓ Ca2+ 2. chronic ↑ osteoporosis 3. ↓ bone protein synthesis, ↓ Ca2+ & PO43- intestinal absorption, &

↑ Ca2+ & PO43 renal excretion 4. Used as Tx in autoimmune diseases – which are more common in

women than in men, and since women are also more at risk for osteoporosis, these tx can be harmful

ii. GH 1. ↑ intestinal Ca2+ absorption

iii. IGF-1 1. ↑ bone protein synthesis

iv. Thyroid hormone 1. promotes hypercalcemia, hypercalciuria 2. can cause osteoporosis

v. Estrogens 1. inhibit [cytokine stimulation of osteoclasts] protective

2. Stimulate calcitonin bone reabsorption protective vi. Insulin

1. ↑ bone formation 2. untreated diabetes ↑ bone loss

Y|Ç

Page 1 of 168 Block I: Homeostasis & Excitable Cellstmedweb.tulane.edu/clubs/owlclub/wp-content/...a.Hypertonic is anything >290mMol/kg b. Hypotonic is anything < 290 mMol/kg

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