Respiratory Physiology Mechanics of Respiration: Overview: • Events in one lung can occur in isolation from the other... • The intrapleural space is filled with liquid (2-10mL) ! two appositional pleura can move with respect to one another. • In steady state the rate of O 2 consumed and CO 2 produced by tissues of the body matches their respective rates of removal from or addition to alveolar gases. • Structure of the Airway: o Nose ! mouth ! pharynx ! larynx ! trachea ! two branches ! 20-23 divisions ! 5 million terminal alveoli. " Trachea is surrounded by horseshoe shaped cartilage " Bronchi have broken rings or plates of cartilage surrounding them " Bronchioles have no supportive cartilage holding them open or patent. • Bronchi and bronchioles are subject to collapse. o Alveoli: tiny sacs (one cell layer thick) that provide surface for diffusive gas exchange between lungs and blood. Divisions 17-23 contain alveoli and ! is the respiratory zone (300 million alveoli make up surface of 70m 2 . o Lungs are covered by the visceral pleura and the chest wall by the parietal pleura. The Intrapleural space is filled with a small volume of intrapleural fluid (2-10mL) ! the two appositional pleura can move with respect to one another o Equilibrium volume (end of quiet expiration) is called the functional residual capacity (FRC). " At FRC, the tendency of the lung to recoil is exactly balanced by the tendency of the chest wall to expand and therefore the lungs remain inflated. • Change in volume from FRC requires use of respiratory muscles. • If air/blood is introduced into the intrapleural space (pneumo-/hemothorax), P IP rises until it reaches P ATM ! chest wall expands and lung recoils (until distending pressures are zero). • P IP is made less negative by any factor that decreases lung elasticity (age, emphysema, etc). Compliance: • A compliance curve is generated by plotting lung volume against distending pressure (P alv - P IP) (compliance is the slope of the curve). Compliance of the lung decreases at large lung volumes. • When the distending pressure for the lung is zero, it still contains air; it is not completely collapsed. • C=!V/!P • Musculature of the Chest Wall: o Inspiration: external intercostals (pull lower ribs toward upper ribs) and diaphragm (moves down, increasing vertical dimensions of the thorax). o Expiration: internal intercostals and rectus abdominus. " During respiration, the lung and chest wall move together because of interpleural cohesive forces (see above). Elastin-collagen latticeworks allow for expansive properties. • Distending Pressure and Functional Residual Capacity (FRC): o Distending (transmural) Pressure: P inside - P outside = P Alveolar - P Intrapleural. This is caused by a decrease of pressure outside of the lung (P IP ). " P IP is negative (subatmospheric) because the lung, which adheres to the chest wall by a thin layer of fluid, tends to recoil, pulls intrapleural space (causing P IP to fall). " The larger the lung volume, the greater the lung recoil forces, and the lower the P IP . Lung Volume Tendency of the lung to recoil (white arrow) is balanced by that of the rib cage to spring out (black arrow). P IP is subatmospheric. Pneumothorax, which occurs when the intrapleural space becomes atmospheric, allows the lung to collapse and the thorax to spring out until the distending pressure for each is zero. The pressure in the air space is greater than total venous gas pressue ( ! recovery) During contraction, !V! … P A 1/" Volume. During inspiration, P A ~ -2. P IP is measured via an esophageal balloon. ) ( IP alv L L P P V C ! " " = • With saline, V max is reached at lower pressure. # surface tension is eliminated by surfactant. Lung compliance (slope) differs at different pressures ! #C at mid-lung pressure/inflation. • Hysteresis (path-dependent compliance): inflation and deflation curves of the air-inflated lung are not the same (due to surface tension/surfactant – at least in part). - Emphysema and age ! C - Edema and ! pulmonary BP # C - ! FRC (obstruction) = ! C = emphysema, asthma - # FRC (restriction)= # C = # surfactant, edema, fibrosis
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Respiratory Physiology
Mechanics of Respiration: Overview:
• Events in one lung can occur in isolation from the other...
• The intrapleural space is filled with liquid (2-10mL) ! two appositional pleura can move with respect to one another.
• In steady state the rate of O2 consumed and CO2 produced by tissues of the body matches their respective rates of removal
from or addition to alveolar gases.
• Structure of the Airway: o Nose ! mouth ! pharynx ! larynx ! trachea ! two branches ! 20-23 divisions ! 5 million terminal alveoli.
" Trachea is surrounded by horseshoe shaped cartilage
" Bronchi have broken rings or plates of cartilage surrounding them
" Bronchioles have no supportive cartilage holding them open or patent.
• Bronchi and bronchioles are subject to collapse.
o Alveoli: tiny sacs (one cell layer thick) that provide surface for diffusive gas exchange between lungs and blood.
Divisions 17-23 contain alveoli and ! is the respiratory zone (300 million alveoli make up surface of 70m2.
o Lungs are covered by the visceral pleura and the chest wall by the parietal pleura. The Intrapleural space is filled
with a small volume of intrapleural fluid (2-10mL) ! the two appositional pleura can move with respect to one
another
o Equilibrium volume (end of quiet expiration) is called the functional residual capacity (FRC).
" At FRC, the tendency of the lung to recoil is exactly balanced by the tendency of the chest wall to expand and
therefore the lungs remain inflated.
• Change in volume from FRC requires use of respiratory muscles.
• If air/blood is introduced into the intrapleural space (pneumo-/hemothorax), PIP rises until it reaches
PATM ! chest wall expands and lung recoils (until distending pressures are zero).
• PIP is made less negative by any factor that decreases lung elasticity (age, emphysema, etc).
Compliance:
• A compliance curve is generated by plotting lung volume against distending pressure
(Palv - PIP) (compliance is the slope of the curve). Compliance of the lung decreases at large
lung volumes.
• When the distending pressure for the lung is zero, it still contains air; it is not completely
collapsed.
• C=!V/!P
• Musculature of the Chest Wall:
o Inspiration: external intercostals (pull lower ribs toward
upper ribs) and diaphragm (moves down, increasing
vertical dimensions of the thorax).
o Expiration: internal intercostals and rectus abdominus.
" During respiration, the lung and chest wall move
together because of interpleural cohesive forces
(see above). Elastin-collagen latticeworks allow
for expansive properties.
• Distending Pressure and Functional Residual Capacity (FRC):
o Distending (transmural) Pressure: Pinside - Poutside =
PAlveolar - PIntrapleural. This is caused by a decrease of
pressure outside of the lung (PIP).
" PIP is negative (subatmospheric) because the
lung, which adheres to the chest wall by a thin
layer of fluid, tends to recoil, pulls intrapleural
space (causing PIP to fall).
" The larger the lung volume, the greater the lung
recoil forces, and the lower the PIP. Lung Volume
" PIP drop
Tendency of the lung to recoil (white arrow) is balanced by that of the rib cage to spring
out (black arrow). PIP is subatmospheric. Pneumothorax, which occurs when the
intrapleural space becomes atmospheric, allows the lung to collapse and the thorax to
spring out until the distending pressure for each is zero. The pressure in the air space is
greater than total venous gas pressue (! recovery) During contraction, !V!… PA 1/"
Volume. During inspiration, PA ~ -2. PIP is measured via an esophageal balloon.
)(IPalv
L
L
PP
VC
!"
"=
• With saline, Vmax is reached at lower pressure. # surface tension is
eliminated by surfactant. Lung compliance (slope) differs at different
pressures ! #C at mid-lung pressure/inflation.
• Hysteresis (path-dependent compliance): inflation and deflation curves of
the air-inflated lung are not the same (due to surface tension/surfactant – at least in part).
- Emphysema and age !C
- Edema and !
pulmonary BP #C
- !FRC (obstruction) =
!C = emphysema,
asthma
- #FRC (restriction)=
# C = # surfactant,
edema, fibrosis
• CL " Ease of lung inflation
• CL 1/" Distending pressure required at any given lung volume.
o $C requires higher than normal distend pressures to expand the lungs. Lung with $ C recoils from the chest wall
more forcibly at any given volume (PIP is more negative) and # inspiratory effort required.
" Emphysema and age ! !C (!compliance ! greater than normal resistance to expiration).
• Surface Tension: significantly effects CL. Surface tension (attractive forces between water molecules) impel air-water
interfaces to have minimum surface area ! # recoil forces in alveoli ! shrinkage (resist expansion).
o Pressure exerted by an alveolus 1/" Radius at a given surface tension (Law of Laplace).
• Compliance of the Lung and Chest Wall:
o Transmural (distending) pressure across the chest wall and lungs together = (Palv - Patm) - in cm H2O
o Transmural (distending) pressure across the chest = (PIP- Patm)
o Transmural (distending) pressure across the lung = (Palv - PIP). " At FRC, transmural (distending) pressure across the combined chest and lung is zero (force of the elastic recoil
of the lung is balanced by that of the chest wall expanding outward).
• At greater volumes, transmural pressures across the combined lung and chest wall are positive
• At smaller volumes, transmural pressures are sub-atmospheric.
• Transmural pressures across the lung are always positive because the lung tends to recoil inwards.
Transmural pressures across the chest wall are negative because the chest tends to recoil outwards at most
volumes.
o At very large lung volumes (~ 80% of vital capacity), the chest wall is overstretched and instead
tends to recoil inwards.
o Compliance in Series: 1/CT = 1/C1 + 1/C2 etc… ! Compliance of the lung and chest wall is less than that of
either the lung or the chest wall alone.
Respiratory Pressure Cycle (Inspiration, Expiration, and Ventilation):
• Inspiration:
o (1) Prior to lung inflation: PA = 0, PIP = -5cm H2O ! PDistending = PA – PIP = 0 – (-5) = +5
o (2) During inspiration: volume of chest and lungs # ! PIP $ ! PA $ ! PDistending (transmural) # ! pressure gradient that
promotes flow of air into the lungs.
o (3) End inspiration is the state of the lung after pressure gradients between alveolar gases and the outside air are
dissipated and the flow of gases into the lungs has stopped.
" Transpulmonary pressure has risen to +9 cm H2O, i.e., P
alv – PIP
= 0 – (-9) = +9 cm H2O.
" Lung volume is greatest.
• Expiration:
o (1) End Inspiration: Muscles of inspiration relax and lungs and chest wall passively return to FRC. Alveolar air is
compressed and PA exceeds PATM !flows into atmosphere.
o (2) Active Expiration (exercise or forced expiration): Internal intercostals and rectus abdominus increase intra-
abdominal pressure to $ chest volume.
• The law of Laplace states that small alveoli ($radius) have a tendence to collapse into larger alveoli. This is
overcome by surfactant - reduces the surface tension of the aqueous air-water interface proportional to the
area it covers. ! surface tension of an alveolus decreases as the alveolus gets smaller and pressure does not
increase as it shrinks (! alveolar capillary filtration forces $).
• Interdependence states that the tendency of one alveolus to recoil is opposed by the recoil forces of
surrounding alveoli.
• Surfactant is produced by Type II alveolar cells (begins to appear in the lung at the 26th week of gestation.
Deep breathing stimulates production. Comprised of dipalmitoyl phosphatidyl choline (DPPC), and other lipids
and proteins. The effect of surfactant can be replicated by detergents.
• Surfactant lowers surface tension and reduces tendency of alveoli to shrink ! surfactant reduces the pull on
the underlying interstitial fluid (makes the interstitial fluid pressure less negative) ! reduces tendency for fluid
to be drawn out of capillaries ! prevents pulmonary edema. Lack of surfactant ! Respiratory Distress
" Diffusing capacity " number of pulmonary capillaries recruited
" Diffusing capacity " hemoglobin concentration
" Diffusing capacity " surface area of functioning alveoli (! tidal volume)
o RULE: If O2 diffusion is sufficient, then it can be assumed that the CO2
diffusion is sufficient.
Fick’s Law of Diffusion:
T
) - P(PDSAV gas
21
=•
CO2 (more soluble) diffuses through the liquid
phase about 20 times more rapidly than O2 for
a given partial pressure gradient.
Solubility of O2 is linear with respect to pO2.
Abnormal barely reaches
equilibrium (PAO2 =
PcapillaryO2). Grossly
abnormal does not reach
equilibrium. PAO2 does not = PcapillaryO2
Rule: two gases with the same partial pressure in the gas phase will have the
same partial pressure in the liquid phase)
" Diffusion to equilibrium is much faster than 0.75seconds ! in
exercise, blood flow # (blood clearance ~ 0.25 seconds in
capillary) but this is enough time for equilibrium to be reached.
• If the alveolar-capillary barrier is thickened by disease
(interstitial fibrosis or pneumonia) O2 diffusion is
impeded and rate of rise of pO2 is slow and equilibrium
may not be reached (not likely to occur for CO2 given !
solubility).
o The number and size of capillaries can be !
during exercise by recruitment and distension.
o Perfusion Limitation (normal O2, CO2, and N2O):
" Gas equilibrates early along length of pulmonary capillary (PAO2 = PaO2)
" Diffusion of gas can only be ! if blood flow !
• Blood can equilibrate in under 0.3 seconds $ blood flow can double (transit time
0.375 seconds – enough for equilibration of O2) and twice as much O2 would have
been transported.
o Diffusion Limitation (O2-emphysema, fibrosis, and exercise, CO):
" Gas does not equilibrate by the time blood reaches the end of the pulmonary capillary (e.g. in
emphysema, surface area for diffusion $, or fibrosis – thickness #). The partial pressure
difference between alveolar air and pulmonary capillary air is maintained and diffusion
continues as long as the gradient is maintained.
" Transit time was insufficient to allow equilibration and that the limitation on gas exchange
had become diffusion limited.
• Alveolar Ventilation Equation:
o Uses PCO2. If alveolar ventilation is halved and CO2 production is constant, PACO2 and ! PaCO2 will
double. Central chemoreceptors that detect partial pressures of CO2 in blood, and reflexively adjust
ventilation to keep the PACO2 regulated, normally at about 40 mm Hg.
• Alveolar (O2) Gas Equation: complicated because more O2 is normally removed from alveoli than is replaced
by CO2 [the respiratory quotient (R) = VCO2/VO2 (rate of CO2 produced/rate of O2 consumed) is usually less than
1].
Removal of O2 and addition of CO2 “converts” fresh inspired air reaching alveoli to alveolar gas. PIO2 drops to PAO2, and PICO2
(normally 0) increases to PACO2. If R = 1, the quantity of O2 removed from alveoli (i.e., from the alveolar ventilation) equals that of
the CO2 replacing it. PIO2 will, therefore, decrease quantitatively by the same amount that PICO2 increases, i.e., from 0 to PACO2. The
CO2 stores (including that in the form of bicarbonate) are greater than the O2 stores (O2 bound to hemoglobin and myoglobin).
Therefore, the alveolar PCO2 takes longer to come to equilibrium, and during the non-steady state, the R-value of expired gas is high,
as the CO2 stores are washed out. Obviously, the opposite changes occur if alveolar ventilation is decreased.
Transport of O2 and CO2 in Blood: o Numbers:
o PB varies with altitude. PB (Sea Level) = 760mmHg.
o Atmospheric air consists of 21% O2, 79% N2, and CO2 (0.03 to 0.04%).
" Rest VO2 = 250ml/min
" Rest VCO2 = 200ml/min
" Exercise VO2 = 3000ml/min
" R = VCO2/VO2 = 0.8
o Oxygen Transport: carried in two forms – (1) dissolved in liquid (small amount) and (2) bound to hemoglobin o Concentration of oxygen dissolved in arterial blood = 0.32ml O2/100ml blood (0.3%). Gas solubility 1/"
temperature o Hemoglobin is not normally fully saturated with O2. Saturation is a function of PO2.
ACO2
2
P
Hg mm 47
!=
••B
COA
PVV
VA = alveolar ventilation; VCO2 = amount of CO2
produced/minute. PB = barometric pressure;
pH2O=47mmHg (correction for water vapor pressure). Alveolar ventilation 1/" PACO2.
PAO2 = PIO2 – PACO2/R When R = 1; PAO2 = PIO2 – PACO2
PO2 = PB x FractionO2 = 760mmHg x 0.21 = 160mmHg ; CO2 = 0.2-0.3mmHg
If R= 1, hyperventilation causes the #
PAO2 = $pCO2
Alveolar Air Equation:
PAO2 = (760-47)FiO2 –PACO2/0.8
where FiO2 = 0.21; 0.8=R, and 47 = pH20
A-a gradient
can be up to 10mmHg
o Hemoglobin blood concentration = 15 g % (g/100 ml blood). One gram of Hb binds ~1.34mL O2.
Substance O2 (mmHg) CO2 (mmHg)
Dry Air 158 0.3
Arriving at Alveoli (saturated w/ H2O vapor 150 0.29
Equilibrated in Alveoli 100 40
Arterial Blood 100 40
Venous Blood 40 46
o Oxyhemoglobin Dissociation Curve:
o Carbon Monoxide: In addition to binding Hb with an affinity much greater than that of O2, CO shifts the dissociation curve
of the remaining HbO2 to the left. An individual with " of Hb in the form of CO-Hb will be able to unload O2 in peripheral
tissues less effectively than an anemic individual with half the normal amount of Hb
• Carbon Dioxide Transport: CO2 is carried in three forms: (1) dissolved CO2 (HCO3- = 90% of CO2 in arterial blood), (2)
bicarbonate ions, and (3) in combination with protein (carbamino compounds). Of the total venous-arterial CO2 difference
(i.e. CO2 exchanged), about 60% is attributable to HCO3-, 30% to carbamino-Hb, and 10% to dissolved CO2.
(HbO2 / O2 capacity of Hb) x 100 = % saturation of Hb
or
[(total O2 content – O2 dissolved) / O2 capacity of Hb] x 100 = % saturation of Hb
(1) flat portion at the upper-right provides for constant arterial O2 saturation
despite wide fluctuations in PAO2
(2) steep slope in the center allows for the release of a large quantity of O2 from
Hb as PO2 decreases in the tissues (! delivery)
(3) arterial blood is ~98% saturated with O2 means that if we want to increase the
amount of O2 on Hb we have only a 2% increment available.
(4) P50 ~ 26mmHg.
(5) !PO2 of pure O2 delivery (medical ~ 600mmHg) does not saturate Hb
significantly, but puts more O2 into solution (dissolved O2 ! ! delivery).
• Right Shift: # Hb-O2 affinity at a given PO2 (! delivery).
o # pH (!H+), ! temperature, ! [2,3-DPG], !pCO2 (the Bohr
Effect).
" The above bind more strongly to deoxygenated Hb than
to oxygenated Hb. By stabilizing the deoxygenated
configuration, they make O2 binding more difficult.
• Left Shift:! Hb-O2 affinity at a given PO2 (# delivery).
• Myoglobin and fetal Hb have a greater affinity for O2 than does HbA (adult). P50-
myoglobin = 5 and P50 - HbF = 15-20 mm Hg.
• Carbon Monoxide (CO) binds Hb with an affinity of 240x that of O2 ($pCO of ~
0.16 mm Hg, CO occupies ~75% of Hb). In the steady state CO occupies a small
fraction of our Hb (~1-2%).
catalyzed by carbonic anhydrase
#pCO2 drives reaction to right
non-enzymatic
the globin of hemoglobin forms carbamino-hemoglobin in the RBC.
o Total CO2 content is a function of PCO2. Within the usual physiologic range of PCO2, the relation is essentially
linear. The locus of the CO2 dissociation curve depends on the hemoglobin saturation. The lower the saturation of
Hb with O2, the larger the CO2 content for a given PCO2 (the Haldane effect). Uptake of O2 aids in unloading of CO2. Oxygenated hemoglobin is a stronger acid than non-oxygenated hemoglobin and gives up H
+ ions that
combine with HCO3- and drive the carbon dioxide sequence of reactions toward CO2. In the tissues, the Haldane effect (increased CO2 content) is
due to deoxygenated hemoglobin moppping up H+ ions produced when carbonic acid dissociates and by the greater facility of deoxygenated
hemoglobin to form carbamino-hemoglobin, favoring the diffusion of CO2 from the tissue into blood.
Buffers and Respiratory Regulation of pH: - acidity is protected by three lines of defense: (l) body buffers, (2) pulmonary
regulation of [CO2], and (3) renal regulation of [HCO3-] in extracellular fluids by minimizing ! in pH of body fluids and correcting
acid-base balance by appropriate retention or excretion of HCO3- and hydrogen ions.
• Buffers: minimize range of pH ! by giving up or accepting protons. Acids are proton donors and bases are proton
acceptors. The pulmonary system interacts with the buffer system to regulate CO2 content. 50% of the total buffering occurs
inside cells by phosphate and various organic anions, including proteins. This process is slower than extracellular buffering,
(hours rather than minutes). Normal pH = 7.4 and normal [H+] = 40nM/L
o Buffer Pairs:
" HCO3- – H2CO3
" Protein- – H-protein
" HPO4-2
– H2PO4-
" Hb- – H-Hb
o For HA #! H+ + A
- K = [H
+][A
-]/[HA] ; pH = pK + log [A
-]/[HA] ; pH = -log [H
+] ; pK = -log K
o Isohydric Principle: There is only one H+ ion active in any given part of the body at any given time and it is this
single H+ with which every buffer system interacts.
o The Bicarbonate-Carbonic Acid Buffer System:
CO2 + H2O ! H2CO3 ! H+ + HCO3
- ! pH = 6.1 + log [HCO3
- ] / 0.03 pCO2 OR [H
+] = 24 pCO2 / [HCO3
- ]
In the range pH =7.28-7.45, the relationship between pH and [H+] is almost linear with an increase of pH by 0.0l unit corresponding
to a decrease in [H+] of l nanomole/L.
o Pulmonary Regulation of pCO2: protection from acidity afforded by buffering alone is often inadequate in the
absence of pulmonary mechanisms of pH regulation.
" Metabolic Acidosis: ! acid production (or base loss) ! metabolic acidosis. # plasma [H+] detected by
" Metabolic alkalosis: ! hypoventilation: loss of H+ from the body by vomiting. #pH causes reflex $ in
alveolar ventilation and # pCO2 ! generation of H+
and HCO3- ! compensatory $ pH.
Ventilation Perfusion Relationships (V/Q mismatch): • The exchange of O2 and CO2 in the lungs is determined by:
o the ratio between alveolar ventilation (VA) and pulmonary blood flow(perfusion) (Q)
o the rate of O2 consumption and CO2 production (VO2 and VCO2).
o the gas tensions in inspired air and in mixed venous blood
o chemical processes in the blood.
• Causes of Hypoxemia ($PaO2):
o Inadequate (Hypo-) Ventilation:
" Reduced or deficient ventilation of the alveoli per unit time. If O2 consumption is not correspondingly
reduced, hypoventilation results in a reduction in alveolar PO2 and hypoxemia.
o Diffusion Impairment:
" $ diffusing capacity of the lung ! lack of equilibration between PcapillaryO2 and PAO2. (blood-gas barrier is
thickened ! diffusion is so slow that equilibration is incomplete – i.e. diffuse interstitial fibrosis, asbestosis
or a build up of fluid in alveoli as a result of infection).
o Right ! Left Shunt (venous blood bypasses the lung):
" right-to-left shunts (arterial blood is diluted with venous blood).
" natural shunts occur as a result of the return of the bronchial circulation to the left heart via the pulmonary
veins and from the return of some coronary venous blood to the left ventricle via the thebesian veins.
pH
mil
lim
ols
of
str
on
g a
cid
lo hi
The curve has a point of inflection at which
changes in the amount of acid added (or
removed) from the solution has little effect
on pH (at equilibrium point, [A-] = [HA]).
• most common shunts are extra-pulmonary (atrial or ventricular septal defects or a patent ductus
arteriosus).
o the final PO2 that results from a mixing of blood volumes with different oxygen partial
pressures cannot be calculated by simply weight averaging the respective PO2 values.
Calculations require that the content of each of the two streams of blood (venous and
oxygenated) be determined first. After averaging O2 content, the PO2 of the blood mixture
can then be estimated.
" Hypoxemia resulting from sizeable shunts cannot be corrected by breathing pure O2. Hemoglobin carries
most of the O2 in blood and is nearly saturated under normal conditions. Breathing 100% oxygen adds
little additional O2 to hemoglobin, it adds a small additional quantity of dissolved gas, and it adds nothing
to the shunted venous blood $ breathing 100% oxygen can significantly raise the partial pressure of O2 in
the oxygenated blood, but the additional content of O2 is quite small and may not compensate for the
oxygen deficit in the venous blood with which it is mixed.
• Breathing 100% O2 ! !A-a difference with a lack of correction and is thus diagnostically
indicative of a shunt.
o Ventilation/Perfusion Mismatch (effects of gravity):
" PaO2 is slightly less than PAO2 because of mismatching of blood flow and ventilation in various parts of the
lung (and secondarily because of natural right to left shunts) " Normal blood flow to the lung is equal to the cardiac output and is about 5 L/min. Resting alveolar
ventilation is roughly 4L/min. " VA/Q ratio for the lung = 0.8
" There is non-homogeneity in the ratio of ventilation to perfusion in each alveolus (PvO2 and PvCO2 are
fairly homogenous with regard to location within the lung, but alveolar heterogeneity gives locational
individuality to PaO2 and PaCO2 (due to gravity).
• Final arterial values are the summation of all varying individual PaO2 and PaCO2.
" In the normal lung, regional differences in VA/Q ratios are responsible for an alveolar – arterial (A-a)
oxygen partial pressure difference (PAO2 – PaO2) of ~ 4 mm Hg.
• Regional Variation in V/Q ratio:
o Gravity and Ventilation: at any given lung volume, alveoli are more distended at the top of the lungs than at the
bottom. Ventilation is better at the bottom of the lung than at the top.
" Because of gravitational forces, PIP is more negative at the top of the lung than at the bottom (weight of
lung pulls down from the apex of the thoracic cavity – lowered PIP ; weight of the lung compresses the base
– increased PIP). ! a gradient of distending pressures (PA – PIP) from the top of the lung to the bottom.
• Larger alveoli at the top of the lung would be on a less compliant portion of the pressure-volume
curve and would be less distensible than smaller ones at the bottom
• An inspiratory effort that # PIP everywhere in the lung will cause the greatest volume change in
the alveoli with the highest compliance $ for a given ! PDistending, ventilation will greater at the
base of the lung than at the apex.
• By gravity, the basal lung is relatively compressed in its resting state but expands more readily on
inspiration than the apex.
o Gravity and Perfusion – top of the lung is poorly perfused, and the bottom of the lung is well perfused.
Blocked Airway
(restricted ventilation)
Blocked Vessel
(restricted perfusion)
Normal VA/Q # VA/Q – significant $
perfusion can’t deplete O2 or enrich with CO2.
$ VA/Q
Bottom of lung
(similar to venous
pressures)
Top of lung
(similar to
inspired air)
Regional arteriolar
differences are
accounted for in
arteries. That is, the
pO2 of the
pulmonary artery is
the same at the apex and the base.
" Pulmonary circulation has low vascular pressure and low flow resistance. Mean pulmonary artery
pressure is about 15 mm Hg. As blood flows through the pulmonary circulation, frictional forces cause
energy to be lost as heat, and pressures continually drop along the arterial tree, the arterioles, capillaries,
venules and veins.
• Pressures are influenced by gravity as well. For each cm we move upward above the level of the
heart, the hydrostatic pressure in the blood vessels decreases by 1 cm of H2O.
• Distending pressure for vessels within the lung is the difference between the pressure within the
vessel and that within alveoli (Pa - PALV).
• Zone 1 (PA > Pa > Pv): At the top of the lung, arterial pressures would be above alveolar pressure
(when PALV = 0 cm H2O) for only a part of the cardiac cycle. When arterial pressure fell (due to
runoff) below 0 cm H2O, vessels would be compressed and flow would stop ! the pulmonary
artery may be insufficient (during part of the cardiac cycle) to maintain blood flow at the apex of
the lung (when PA > Pa, all downstream vessels are collapsed). Complete cessation of flow
throughout the cardiac cycle does not occur in Zone 1 unless arterial pressure is reduced
(hemorrhage) or if PA is ! (positive pressure ventilation). Ventilated but unperfused areas
contribute to alveolar dead space.
• Zone 2 (Pa > PA > Pv): Ppulmonary artery # because of # hydrostatic pressure (exceeds PA). Pressure in
downstream venules falls below PA and they collapse (thus act as Starling resistors - when venules
collapse and flow stops, fluid energy is no longer dissipated as heat and pressure rises. As soon
as pressure in the vessel exceeds that in the alveoli, the vessel opens and flow is reestablished.
However, with flow, the fluid energy (pressure) drops and the vessel collapses once again.
Pressure in the venule, therefore, oscillates slightly above and below alveolar pressure, and the
gradient for flow effectively becomes the difference between arterial and alveolar pressures)
• Zone 3 (Pa > Pv > PA): pressures have increased by 1 cm H2O for every 1 cm of descent. All
pressures in the vasculature exceed PA, and all vessels remain open. Distending pressures for
vessels is greatest in this zone. Vascular resistance is lowest and perfusion greatest in this region
of the lung.
There is a vertical distribution of VA/Q. The top of the lung is relatively poorly perfused (with respect to ventilation) and the bottom
of the lung is relatively poorly ventilated (with respect to perfusion). Though ventilation (VA) and perfusion (Q) each alone
decrease near the top of the lung, the V/Q ratio improves near the top of the lung. BUT, given the perfusion at the bottom of the
lung, relatively more gas exchange occurs there. At the bottom of the lung, VA/Q approaches zero (little or no ventilation) and at
the top, VA/Q approaches infinity (little or no perfusion – alveolar dead space)
o Effect of Regional Differences of VA/Q on Mixed Arterial Blood - The small amount of oxygen added by the unit
with the high VA/Q ratio (right: PO2 = 100 mm Hg) is inadequate to compensate for the deficit created by the unit
with the low VA/Q ratio (left: PO2 = ~ 38 mm Hg). Overall depression of mixed arterial PO2 to about 50 mmHg (for
a Hb concentration of 15 gm/100 ml). In normal individuals ventilation perfusion mismatch accounts for the small 4
mm Hg (PA - Pa) difference. In the diseased lung, nonuniform distribution of ventilation and perfusion is the main
cause of arterial hypoxemia and hypercapnia.
Point V represents the PO2 and PCO2 of mixed
venous blood (~ 40 and 46 mm Hg). Point I
represents the PO2 and PCO2 of inspired gas (~ 150
and 0 mmHg). Lung units with VA/Q near zero (little
or no ventilation) would reach equilibrium values
near V. Lung units with VA/Q approaching infinity
(little or no perfusion, i.e., alveolar dead space)
Regulation of Respiration: • Peripheral Efferent Impulses:
o Augmenting Behavior: at the onset of inspiration, impulses in fibers innervating
inspiratory muscles # in frequenc and then rapidly $ near the end of inspiration (“ramp-
like”).
o # Depth of Respiration: (1) # frequency of impulses (steepness of ramp#) ; (2)
recruitment (activation of more motor units) ; (3) longer duration of impulse burst
(prolonged inspiration) – # VT but does not # minute ventilation (period of inspiration
and of expiration both increase). Force of contraction is progressively summated during
inspiration until sudden termination .
o Rate of Breathing: Determined by duration of interval between successive discharge and
the duration of the burst of impulses during inspiration (expiratory time " inspiratory
time ! longer, slower breaths ! slower respiratory frequency).
o Muscle Control: During inspiration, the expiratory muscles are inhibited. Only during
forced expiration is there an # excitation of motor units innervating expiratory muscles.
• Central Regulation of Respiration: - rhythmic excitation of respiratory motor neurons depends on impulses arising in
higher centers (bilaterally in the pons and medulla).
o Transection of the brain stem below the medulla results in respiratory arrest
o Transection of the brain stem above the pons limits (but does not abolish) breathing (or the majority of reflex
control)
" Dorsal Respiratory Group [Nucleus of Tractus Solitarius] – associated with inspiration
" Ventral Respiratory Group [medulla] – associated with inspiration and expiration
" Pneumotaxic Center (Pontine Respiratory Group) [pons] – provides early cut-off of inspiration
• Removal of input from the vagus or from the pontine respiratory group ! ! depth of respiration
and # respiratory frequency.
o If both inputs are removed, apneustic breathing results (prolonged inspiratory period
interrupted by brief expiratory gasps).
o Self-Cycling Firing/Quiescence Cycle Regulation: primarily in the Dorsal Respiratory Group.
• Modulation of Neural Control: #pO2, !pCO2, #pH (![H+]) all ! ! ventilation (to return values to normal – PaO2 =
100mmHg, PaCO2 =40mmHg, and pH = 7.4)
o Chemical Factors:
" Chemoreceptors monitoring arterial PO2, PCO2 and pH: Chemoreceptors excite inspiratory PMN and
inhibit the offswitch (C) ! ! VE (minute ventilation).
• Peripheral: Carotid and Aortic bodies (100% of pO2 regulation, 80% of pH regulation, and 10%
of pCO2 regulation).
• Central: ventral surface of the medulla near the exit of CN IX and X. Chemicals reaching central
receptors are determined by the blood brain barrier.
o Changes ventilation due to PO2 and pH result from stimulation of the peripheral
chemoreceptors. The central chemoreceptors modulate ventilation primarily in response
to CO2. Central chemoreceptors detect changes in the acidity of the CSF that baths the
- The medullary inspiratory neuron (A) sends descending fibers to respiratory motor
neurons in the C-spine (phrenic) and sends processes that synapse and stimulate other
medullary neurons (B). B sends processes to an inhibitory interneuron (C), the off-
switch, which synapses on, and inhibits the inspiratory neuron (A). A ! activates
inspiratory motor activity and generates an inhibitory input to itself (negative feedback
loop). The inhibitory interneuron (C) also receives input from the pontine respiratory
group (pneumotaxic center) to aid in controlling duration and depth of inspiration.
- Hering-Breuer Reflex: Pulmonary stretch receptors (in the airway smooth muscle
layer) are activated by lung inflation. Afferent APs travel in the vagi and activate B
neurons (# activation of the off-switch) ! # termination of inspiration. Tidal volume
must be at least 1L to invoke the Hering-Breuer reflex (so adults can take deep and !
frequency breaths).
- Neurons in the VRG have expiratory phase firing patterns that reciprocally inhibit
inspiratory neurons and vice versa (accounts for the lack of firing of inspiratory neurons
during expiration, and vice-versa)- The Pre-Botzinger Complex (neurons in the rostral
portion of the VRG) have pacemaker activity and fire at the onset of inspiratory activity
(central pattern generators)
neurons (CO2 crosses the blood-brain barrier and ! CSF pH is influenced by changes in
arterial PCO2)
o Changes in CO2 are more effective in changing ventilation than are changes in O2.
(Effects of gas partial pressures on ventilation are most pronounced when PO2 and PCO2
change reciprocally (when PO2 decreases as PCO2 increases and vice-versa).
• CO2: ! PCO2 is much more effective in increasing ventilation than # in PO2. (! PCO2 of as little as
3 mm Hg ! doubled ventilation).
o Relationship between ventilation and PCO2 rises steeply and reaches a maximum when
PCO2 is about 70-80 mmHg. o At # levels, ventilation $ because of the toxic effects of high CO2 on central neuronal
function. Inactivation of carotid and aortic bodies does not abolish or even significantly
reduce the total respiratory response to inhalation of CO2.
o Central chemoreceptor response to CO2 is mediated through !s in [H+] of the CSF (via
carbonic anhydrase and a carbonic acid intermediate) ! when [CO2] # in arterial blood,
[H+] in CSF # ! activation of central chemoreceptors.
" $ pH of CSF as a result of chronic # PCO2 leads over time to a compensatory #
[HCO3-], returning pH of CSF toward normal and shifting the sensitivity of the
receptors so that they operate over a higher range of PCO2.
" When PaCO2 is chronically $ (high altitude), ! in CSF-HCO3- are in the
opposite direction, and sensitivity of the chemoreceptors is shifted to lower
ranges of PCO2.
" ! arterial pH is ineffective in activating central chemoreceptors, because the
blood-brain barrier prevents H+ from entering the CSF.
• O2: carotid bodies are more important than the aortic bodies as respiratory regulatory organs.
o Aortic and carotid bodies are relatively insensitive to ! PO2 (changing the fraction of O2
in air from 21% to as low as 12-14% doesn’t change ventilation significantly). At
fractional O2 content less than 10%, # ventilation is pronounced " Type I glomus cells contain O2 sensitive K
+ channels (close when O2 levels $ !
depolarization of the cells) ! opening of voltage gated Ca2+
channels and influx
of Ca2+
! transmitter release and activation of the afferent nerves fibers
" Chemoreceptor blood flow is enormous (40x that of the brain)
" Normally, PaO2 levels are monitored, not the oxygen content of the blood.
When flow $ substantially (hemorrhage), AB and CB respond with increased
electrical activity even though PaO2 may be normal. (Large $ flow produces a
local $ in PO2 that depolarizes the glomus cells).
• Glomus cells contain K+ channels that are closed not only by low levels
of O2, but also by $ pH of the cell (can result from # pCO2 or
metabolic acidosis). Subsequent depolarization will trigger transmitter
release and activation of afferent fibers.
o Denervation of the CB and AB results in complete loss of the respiratory response to !
PaO2, while the response to PaCO2 remains unchanged. Respiratory response to changes
in pO2 derives entirely from the peripheral chemoreceptors, while that for CO2 is
regulated by central chemoreceptors.
• [H+]: # [H
+] ! # tidal volume and frequency (not as sensitive to pH as to O2/CO2
o AB and CB respond to $pH (major portion of respiratory response to ! arterial pH)
Until pO2 is less than 60mmHg, Hb saturation ~
90% … Below this, ventilation # $ humans are
not as sensitive to O2 as to CO2. !pCO2 ! neural
toxicity (CO2 narcosis).
The response to both gases is greater than the
sum of individual responses (synergistic)
" Central chemoreceptors have a role in response to large ! arterial pH (H+ may
be able to cross the blood-brain barrier through very infrequent “breaks”).
o Other Inputs to the Respiratory Center: " Cerebral cortex: can initiate voluntary respiratory activity that can # minute ventilation to 160 L/min. " Hypothalamic centers and the limbic system: can be activated by emotional states (anxiety, fear or stress)
! # ventilation.
• Temperature receptors (hypothalamic and skin): ! # ventilation when body temperature #.
Helps the body lose heat by warming inspired air.
" Receptors in muscles and joints: cause # ventilation with exercise or simply when limbs are moved
passively. E.
" Protective reflexes (sneezing and coughing)
" Medullary areas: block respiration during swallowing and vomiting.
" Activation of baroreceptors: ! $ respiration when BP #, and # respiratory activity when BP$.
• Lung Receptors:
o Stretch Receptors (in airway smooth muscle): # activity during inspiration and cause # firing of vagal afferents to
the medullary respiratory control center (Hering-Breuer reflex). The inflation reflex is well-developed in newborn
babies; it $ in effectiveness during the first 5 days of life. The reflex is weak in adults (unless the lung inflation is
1L or more). o Irritant receptors (between airway epithelial cells): respond to noxious gases, ammonia, cigarette smoke, other
particulate material and agents such as histamine. " Vagal afferents ! reflex bronchoconstriction and hyperpnea.
o J Receptors (in conducting airways and alveoli): respond to chemical and mechanical stimulation.
transferrin, lipoproteins), heat, H+, and H2O (among others).
" Centrifugation of blood ! solid red layer at the bottom (RBCs), a yellowish layer at the top (plasma), and a
tan interface (the “buffy” layer – platelets and leukocytes.
• % hematocrit = height of whole blood / height of RBCs.
o Male: 42-52%
o Female: 37-47%
• A unit of blood = 500ml (75ml/kg)
o Male: 5.2L
o Female: 3.3L
o Carrier Proteins: Triglycerides (lipoproteins), fatty acids (serum albumin), iron (transferrin), bilirubin (serum
albumin), thyroxine – thyroid hormone (thyroid binding globulin). o Transport of O2: Transport of O2 principally via the carrier protein hemoglobin (15g Hb/100ml of blood). This is
three times the amount of all the other plasma proteins combined.
• Erythrocytes:
o Overview:
" Produced by precursor cells in bone marrow. Has no nucleus, no ribosomes, and no mitochondria and ! is
essentially a biconcave sac filled with a 30% Hb solution (plus other enzymes and smaller molecules).
" Incapable of synthesizing proteins or lipids or of carrying out oxidative metabolism.
" Survives for ~120 days despite repeated deformations throughout circulation and despite repeated exposure
to # turbuence.
• Loss of deformability upon aging leads to death of the RBC.
" The overall function of erythrocytes is to protect Hb from denaturation and degradation. The lifespan of
hemoglobin in the red cell (intracorpuscular hemoglobin) is the same as the lifespan of the RBC (120 days).
In the absence of a protective envelope, Hb rapidly disappears from the plasma (lifespan of seconds or
minutes).
• In whole blood: 15g Hb/100ml blood
• HCT = 50%
• In RBCs: 30g Hb/100ml cytosol (30% concentration)
o Borderline crystallization (a la sickled RBCs)
o Structure: Flat biconcave disk (8µm x 1µm x 1µm) NOT spherical
" A sphere has the worst possible surface area/volume ! deformation ! # SA ! # surface tension ! #
tearing of membrane (spherocytosis) ! RBCs are flat for protection ! $intracellular time of diffusion to
and from Hb (O2 loading and unloading).
o Metabolism: Insulin Independent
" 90% of RBCs energy is derived from anaerobic glycolysis (conversion of glucose to lactic acid). The
remainder comes from the hexose monophosphate shunt (the phosphogluconate pathway).
• ATP derived from glycolysis powers the Na+-K
+-ATPase (maintains Na
+ and K
+ gradients !
keeping H2O out).
o ~30% of RBCs energy resources may be thus devoted.
• ATP also fuels active removal of calcium from RBCs. Buildup of calcium ions causes cross-
linking of RBC membrane proteins and decreased deformability of the cell.
o NADPH (from phosphogluconate pathway) drives reduction of glutathione (GSSG).
Reduced glutathione (GSH) protects the cell membrane and hemoglobin against
oxidants. Oxidation of sulfhydryl groups (H2O2) associated with RBC membrane
proteins ! # increased stiffness and fragility of older cells. Fe2+
can also become Fe3+
(methemglobin – metHb – cannot bind O2).
" ATP depletion ! RBC crenation (deformation), swelling (H2O influx), and $
deformability (due to Ca2+
sedimentation). • Principal task of the erythrocyte -- transport of oxygen and carbon dioxide -- does not require
energy (relies on passive diffusion ). Energy is utilized primarily in maintenance functions in
the mature erythrocyte (strong correlation between drop in ATP concentration and impaired
survival in older red cells).
o Erythropoiesis (production of RBCs): At time of birth, almost all RBCs are produced by bone marrow. As we age,
marrow components of long bones become filled with fat. Erythropoiesis is a self-sustaining system (maintenance on
stem cells puts RBCs at risk – chemotherapy/radiation).
" Precursors:
• (1) Pluripotential Stem Cells: give rise to erythrocytes, platelets, monocytes, granulocytes, and
lymphocytes.
• (2) Committed Stem Cells: develop from pluripotential cells and give rise only to one type of
blood cell.
o Committed stem cells give rise to normoblasts (make Hb), which undergo four
differentiating divisions (~five days). Hb synthesis occurs in normoblasts (all
maturational stages) until concentration is 20g/100ml at which point cell division stops
and the reticulocyte is produced ! circulation (five days after differentiation).
" Ribosomes, ER, and mRNA keep making Hb for ~2days in the reticulocyte
form, then the cellular machinery breaks down ! biconcave shape.
o Reticulocyte Index: Normally ~ 2% of all RBCs are reticulocytes. # when production of
RBCs is #.
o Regulation of Erythropoiesis: Regulation of [RBC] is via rate of production, not rate of hemolysis.
" # Erythropoiesis due to:
• (1) # size of erythroid marrow compartment (#total number of erythrocyte precursors)
• (2) # rate of maturation of erythrocyte precursors
o Both of the above are stimulated by erythropoietin.
Lactose Dehydrogenase Renewal
" Erythropoietin production ! (from endocrine cells in kidney) due to #pO2.
Erythropoietin stimulates erythropoiesis during day-to-day regulation of RBC
output (in addition to hypoxic crisis). EPO also stimulates Hb synthesis by
normoblasts.
• If one kidney is failing, it can perceive #pO2 ! !erythropoiesis !
abnormally ! [RBC].
o Hemoglobin Synthesis/Iron Metabolism:
" Hemoglobin:
• Globin: tetrameric protein consisting of two molecules, each of two different polypeptide chains
($ and %-globin)
• Heme: porphyrin ring structure containing iron which binds oxygen (in Fe2+
form).
o There are four heme groups, four iron molecules, and four O2 binding sites per Hb
molecule. " and %-globin are synthesized on ribosomes in the cytosol of normoblasts.
The porphryin group is synthesized in the mitochondria of normoblasts.
• Sources of Iron: salvaged from degraded red blood cells > mobilized from body stores > dietary
iron
o Iron is complex with transferrin in the blood. Fe-Transferrin enters marrow and binds on
a normoblast surface receptor. Iron is incorporated into Hb and transferrin returns to
plasma. Iron is stored bound to ferritin or hemosiderin.
o Regulation of iron levels in the body is exerted by rate of intestinal absorption of iron at
the level of the mucosal cells (enterocytes) in the GI tract. It can be retained in mucosal
cells as ferritin complex and eliminated as cells slough into feces or it can bind reversibly
to mobilferrin !ferroportin ! transferrin complex.
" Iron absorption is influenced by the amount of apoferritin (synthesized by
mucosal cells). (! when body iron stores are abundant and # when body stores
are depleted. Translation of the apoferritin mRNA that is regulated by the
cytosolic iron concentration.
" Hepcidin is the principal regulator of the absorption and systemic distribution
of iron. It binds ferroportin (basolateral membrane of enterocytes) and initiates
degradation. If [hepcidin] !, little ferroportin is available to permit iron
absorption. Hepcidin synthesis ! by conditions producing iron loading and #
by anemia, hypoxia or ! erythropoiesis.
o RBC Destruction: 10% intravascular hemolysis (Rh-incompatibility, transfusion reactions, etc) and 90%
" Hb and other RBC proteins are degraded to amino acids (reutilized for protein synthesis). Iron may be
temporarily stored (within the macrophage) and is released and bound by transferrin (returned to the
marrow or other stores). Porphyrin group is degraded via the bilirubin pathway. Hb dissociates into dimers,
which bind to serum protein haptoglobin. During severe intravascular hemolysis, the capacity of
haptoglobin to bind Hb dimers is exceeded, the plasma haptoglobin becomes depleted, and a portion of Hb
may appear in the urine (hemoglobinuria), which will turn dark. If intravascular hemolysis #, Hb-tetramers
! methemglobin ! globin or heme (! liver via hemopexin).
• The conversion of porphyrin to bilirubin yields carbon monoxide ! measurement of CO in
expired air provides an index of # hemolysis.
• Anemia: insufficient number of circulating red blood cells or insufficient amount of circulating Hb. Anemia can develop if
rate of RBC production is abnormally #, if the rate of RBC destruction of red cells is abnormally !, or both. Anemia also
results from acute loss of blood
o Inadequate erythropoiesis: " Iron Deficiency: Rarely occurs in males except
after bleeding episodes. Fairly common in females
due to loss of iron in the menstrual flow, and, during
pregnancy, because of the relative iron deficiency
resulting from the demands of fetal erythropoiesis.
Treated by giving iron.
" Vitamin B12 Deficiency/Pernicious Anemia:
Inability to absorb B12 (failure of intrinsic factor).
Treated by parenteral B12 administration.
" Folic Acid Deficiency:
• B12 and folic acid deficiency are necessary
for polynucleotide biosynthesis $ for
proliferation of erythrocyte precursors in
marrow (lack of maturation of erythrocytes.
" Diseases of Bone Marrow: Failure of marrow to produce erythrocytes often results from unknown causes (i.e.
chemotherapeutic agents and radiation). These agents destroy stem cells and deplete marrow of its primary erythrocyte
precursor cells.
" Defective Hb Synthesis: Thalassemia (" and % globin chains are not synthesized in equal amounts) ! destruction of
erythrocyte precursors in the marrow. &-globin (fetal) can be upregulated to replace %-globin.
" Inadequate Erythropoietin: results from renal or liver disease.
o Abnormal Rate of RBC Destruction: Abnormally rapid destruction of RBCs is called hemolysis (hemolytic
anemia). Marrow has the capacity to expand its rate of production of RBCs by 6x. With normal marrow function,
! erythropoiesis $ partly compensates for hemolytic conditions in which the life span of circulating erythrocytes is
only 20 days
" Factors # lifespan of RBCs:
• Genetic abnormalities of RBC membrane ! rigid or fragile cells
o Hereditary Spherocytosis: RBCs are spherical and rigid. They suffer damage while passing
through the spleen. Treated by splenectomy.
• Genetic abnormalities of Hb
o Sickle Cell Anemia: One Glu!Val in the %-chain of Hb. In response to #pO2 and #pH, Hb
polymerizes and RBC assumes a rigid (sickled) shape. Sickled cells are trapped in
microvasculature and the spleen.
• Genetic abnormalities of RBC metabolism o Glucose-6-phosphate deficiency: activity of the hexose monophosphate shunt is # ! # production
of NADPH and reduced glutathione. RBCs are sensitive to oxidizing agents ! hemolytic crises. • Presence of antibodies against RBC surface antigens ! lysing
o Rh-incompatability
• Lytic agents released by bacteria
• Blood Grouping/Typing:
Hemostasis: (1) Vasoconstriction, (2) Platelet Plug Formation, (3) Blood Coagulation, (4) Control and Limitation of Clotting
• Vasoconstriction: (crushing injuries bleed less than cutting injuries) – vasoconstrictive response " damage
o Myogenic/Neurogenic Vasospasm (immediate smooth muscle reaction):
" Immediate local vasoconstriction (several cm on either side of the injury site) – may cause almost complete
cessation of flow.
" Pain receptors can trigger spinal reflexes ! # sympathetic firing and # vasoconstriction.
• Myogenic and neurogenic vasospasms follow injury immediately and help prevent acute blood
loss.
o Lasts no more than 20-30 minutes.
o Humoral Response (serotonin and prothrombin released at site of injury – minutes later):
" Serotonin (5-HT), thromboxane A2, and prostoglandins all cause vasoconstriction
• Humorally triggered vasoconstriction rapidly follows injury (but slower than
myogenic/neurogenic vasospasm)
o Lasts up to several hours.
o Pre-Capillary Sphincter Plugs: control blood loss at the capillary level by contraction of the muscle sphincters at
the junctions of met-arterioles and the capillaries.
• Platelet Plug Formation: when a wall defect forms, platelets in the vessel bind subendothelial collagen (platelet adhesion)
outside of the defect. Binding ! conformation ! ! granular exocytosis (release reaction – ADP, Ca2+
, and serotonin
released, and Phospholipase A2 activated ! Thromboxane A2.
AB = universal recipient
O = universal donor
Rh Blood Group (D antigen):
- Cells which bear D antigen are termed Rh-positive; cells without
D antigen are termed Rh-negative. When an Rh+ father and an Rh
-
mother conceive an Rh+ fetus, RBCs from the baby introduce D-
antigens into maternal circulation (at birth), antibodies against the
D-antigen form in the mother (anti-D antibodies develop after birth)
! in subsequent pregnancies with an Rh+ fetus, maternal anti-D
antibodies cause erythroblastosis fetalis (fetal hemolysis).
- At time of birth of an Rh+ child, an Rh
- mother can be treated with
rhogam (D-antibodies). These injected antibodies remove D-
antigen from maternal circuation ! prevent maternal immune
system from detecting the antigen and prevent maternal antibody
production (the injected antibodies degrade).
o (1) Platelet Adhesion: Platelets bind Von Willebrand Factor (made by endothelium), which is in turn bound to
collagen [VWF coats collagen and binds Factor VIII for coagulation – VWF disease is common (~10% of
population) and may or may not include some combination of platelet adhesion or coagulation defecits.
o (2) Release Reaction: ! shape and release of storage granules.
" Diacylglycerol (DAG) and Inositol triphosphate (IP3) are platelet 2nd
messengers.
• DAG activates C-kinase and IP3 ! release of intracellular Ca2+
.
o Synergistically, DAG and IP3 # release reaction.
" Release reaction ! #ADP, Ca2+
, Serotonin, and activation of Phospholipase A2
(! Thromboxane A2).
• Thromboxane A2 and ADP ! # platelet-platelet adhesion (platelet
aggregation) and # release reaction (! positive feedback ! #
Thromboxane A2 and ADP release).
o Platelet aggregation does not normally extend away from the site of injury because the endothelial cells of the
surrounding vessels produce an inhibitor of aggregation (prostacyclin – PGI2).
o Aspirin (acetylsalicylic acid) inhibits thromboxane A2 formation ! no clotting:
" acetylates and inactivates the enzyme cyclo-oxygenase (required for thromboxane A2 formation). The
function of a given platelet is irreversibly depressed following exposure to aspirin.
• Blood Coagulation (secondary hemostasis):
o Fibrinogen ! Fibrin (protease activation to fibrin monomers, which spontaneously aggregate to polymers with
assistance of fibrin stabilizing factor – CF VIII) forming the strong cables of a clot).
" The Fibrinogen ! Fibrin reaction is driven by thromboplastins (activated by platelets) and Ca2+
.
• Thromboplastins = Clotting Factors
Clotting factor Synonym
I Fibrinogen
II Prothrombin
III Thromboplastin
IV Calcium
V Proaccelerin, labile factor
VII Proconvertin, stable factor
VIII Antihemophilic factor/globulin, antihemophilic factor A
IX Plasma thromboplastic component, Christmas factor, antihemophilic
factor B
X Stuart Prower factor
XI Plasma thromboplastin antecedent, antihemophilic factor C.
XII Hageman factor, glass factor
XIII Fibrin stabilizing factor, Laki-Lorand factor
o Intrinsic Pathway: all involved factors are found in the blood
" The cascade system has tremendous amplification potential (but breakdown at any step ! inhibition of the
system).
• The intrinsic pathway has a requirement of Ca2+
and platelets.
• There are positive feedback loops within the system (fibrinogen cleaves V ! Vactive)
" Contact Activated by the binding of clotting factor XII to the subendothelial connective tissue exposed by
blood vessel injury (along with prekallikrein, kininogen, and factor XI).
Factor XII undergoes structural ! and with kininogen (cofactor) digests prekallikrein ! kallikrein. Kallikrein cleaves factor XII !
XIIa (kininogen – cofactor). Factor XIIa and kininogen cleave factor XI ! XIactive. Factor XIa activates Factor IX ! IXa (with Ca2+
- cofactor), which is bound to phospholipids (platelet factor three – PF3) on the surface of aggregated platelets. Factors VIII and IXa
are bound to PF3 along with Ca2+
and Factor X ! Xa. While bound to PF3 Prothrombin (II) is cleaved to Thrombin (IIa) in the
presence of Ca2+
(Factor V – cofactor) by Xa. Thrombin cleaves fibrinogen to produce fibrin (monomers). Fibrin then freely
polymerizes to form fibrin. Polymers are rapidly strengthened and stabilized by the formation of covalent bonds within fibrin strands
and between different strands under the action of factor XIII (itself activated by thrombin).
o Extrinsic Pathway: one extrinsic component - tissue factor/tissue thromboplastin (derived from adventitia of
blood vessels – not normally exposed to blood)
" following an injury in which blood extravasates, tissue factor binds to and activates the blood factor VII.
Deficiency of
factor
Syndrome
I Afibrinogenemia (can be
congenital - rare)
II Hypoprothrombinemia
(usually as a consequence of
vitamin K deficiency)
V Parahemophilia (congenital)
VII Hypoconvertinemia
(congenital)
VIII Hemophilia A (congenital -
sex-linked)
IX Hemophilia B (Christmas
disease) (congenital)
X Stuart-Prower factor
deficiency (congenital)
XI PTA deficiency (congenital)
XII Hageman trait (congenital)
VIII Deficiency is Classic Hemophilia
Following tissue trauma with blood extravasation, tissue factor (Ca2+
and phospholipids – cofactors) cleaves Factor VII ! VIIa.
Factor VIIa activates Factor X ! Xa (in the presence of Ca2+
and phospholipids). Factor Xa activates more Factor VII (positive
feedback loop). Prolonged digestion by Xa ultimately inactivates factor VII (delayed negative feedback regulatory loop). Factor Xa
acts as above.
" Role of Calcium Ions:
o Critical for calcium binding by various factors (II, VII, IX, and X) is the presence of &-carboxyglutamic acid
(GLA) residues in the amino acid sequences of these proteins. Vitamin K is required for carboxylation (post-
translational modification) to form these GLA residues. In the absence of vitamin K there is no calcium binding
by Factors II, X, VII and IX ! there is no coagulation.
" Coumadin (anticoagulant) blocks enzymatic formation of GLA residues ! factors in the circulation
cannot bind Ca2+
and ! coagulation is impaired.
• EDTA/Citrate block Ca2+
in blood tubes (preventing coagulation in blood being sent to labs).
" Control and Limitation of Clots:
o Clearance of Clotting Factors by Blood Flow:
" As blood vessels dilate (site of injury is normally vasoconstricted) activated clotting factors diffuse (or
are transported) away and they are readily diluted and removed by normal clearance mechanisms.
o Antithrombins (potentiated by heparin):
" "-2-globulin antithrombin III binds to and inhibits thrombin and activated factors IX, X, XI and XII.
Its activity is enhanced over 1000X by the presence of heparin.
o Protein C:
" Protein C limits clotting and is activated by thrombin. Thrombin only becomes active against this
target once it is itself bound to the protein thrombomodulin (a thrombin receptor protein on the surface
of endothelial cells). When bound to thrombomodulin, thrombin does not act on fibrinogen, but
instead activates protein C.
" Protein C (and protein S), inhibits clotting factors VIII and V
• ! Thrombin directly activates factor VIIIa and Va but also inactivates them, indirectly,
through proteins C/S.
o Tissue Factor Pathway Inhibitor:
" Produced by endothelial cells, TFPI binds to and inactivates VIIa (inhibits extrinsic pathway).
o Plasmin (Fibrinolysin):
" Plasmin is a proteolytic enzyme present in the circulation as an inactive proenzyme (plasminogen).
Tissue plasminogen activator (tPA) is released from endothelial cells following injury and cleaves
plasminogen ! plasmin (Factor XIIa – cofactor).
" Plasmin degrades fibrin and fibrinogen (! dissolves clots).
• Genetically expressed tPA is used to degrade clots in the coronary artery.
" Degradation of fibrin by plasmin is also an important means of remodeling and breaking down the clot
during the healing process.
o Plasminogen Activator Inhibitors (PAI) and Antiplasmin: help to modulate the fibrinolytic action.
o Angiostatin: derives from part of the plasminogen molecule and inhibits growth of blood vessels
Renal Physiology and Homeostasis Renal Organization and Function:
" Primary Functions of the Kidneys: (1) Regulate volume and composition of ECF (concentration of inorganic ions,
osmolality, and acidity) in order to maintain homeostasis, (2) Excrete metabolic waste products (urea, uric acid, and
creatinine), end products of Hb degradation, and foreign chemicals (drugs, food additives, and pesticides), and (3) Produce
circulating factors (erythropoietin, renin, and 1,25-dihydroxyvitamin D3).
" Structural Organization:
o Two retroperitoneal organs (in the back of the abdominal wall). Urine flows from kidneys ! ureters ! bladder !
elimination during micturition (via the urethra)
o Each kidney contains ~1 million nephrons.
The extrinsic pathway (contact activation) represents the main trigger for coagulation. Once triggered, the end product of the
pathway, thrombin, has a positive feedback action, activating intermediates of the intrinsic pathway, XI and VIII, which then
amplify the response, producing far greater amounts of thrombin. Thrombin can also activate V and, as noted above, XIII. Once
tissue thromboplastins mix with the blood, thrombin is released rapidly, and clotting by the extrinsic pathway may require only
10-15 seconds as opposed to the 1-3 minutes required by the intrinsic system.
o Tubular fluid from nephrons ! collecting ducts ! pyramids ! papillae (tips of pyramids) ! calyces ! renal
pelvis ! ureter. Pyramids contain the collecting ducts, loops of Henle, and vasa recta
o Blood Supply: Renal artery divides ! interlobar and arcuate arteries ! interlobular arteries ! Afferent
arterioles (perpendicular to interlobular arteries – each supplies blood to a single nephron) ! glomerulus
(glomerular capillary bed) ! efferent arteriole ! peritubular capillaries and vasa recta (lg. capillaries from
which emerge a network of small capillaries surrounding the medullary tubular system – less flow than cortical
Reabsorption of Sodium, Glucose, and Water: " Sodium: 67% absorbed in proximal tubule (PT), also reabsorbed at the thick ascending limb (TAL) the distal tubule (DT),
and the collecting duct (CD). All sodium transport is transcellular. Entry into the cell is always downhill and basolateral exit
is always uphill (Na+-K
+ - ATPase). 90% of energy used in the kidney is used for Na
+ transport (basolateral).
o PT:
" Early: co-transport with organic solutes (glucose, amino acids, lactate, phosphate, etc) and via a Na+ - H
+
exchanger.
" Late: Na+-H
+ exchanger is coupled with a Cl
- —
OH- exchanger (net NaCl reabsorption).
o D-LOH: impermeable to Na+
o TAL: Na+-K
+-2Cl
- co-transporter and Na
+-H
+ exchanger
o DT:
" Early: Na+-Cl
- cotransport (thiazide sensitive)
" Late: epithelial Na+ channel (amiloride sensitive and aldosterone regulated)
o CD: epithelial Na+ channel (amiloride sensitive and aldosterone regulated)
" Glucose: 100% reabsorbed in the proximal tubule via energy-free coupling with Na+ transport. SGLT2 is a low-affinity/high-
capacity transporter (1:1) in the early PT. SGLT1 is a high-affinity/low capacity transporter (2Na+:1glucose) in the late PT.
Glucose exits basolaterally by facilitated diffusion through two Na+-independent transporters (GLUT2- early PT; GLUT1 –
late PT).
When Na+ binds SGLT1/2, the affinity for glucose ! drastically. The
kidneys do not regulate plasma glucose, they simply absorb what is
available until Transport Maximum (Tm) is reached. If plasma glucose
increases to high values (normal = 1g/L) - such as diabetes mellitus,
filtered load exceeds capacity of the tubules to reabsorb glucose. !
transporter saturation ! unreabsorbed glucose appears in the urine.
Tm for glucose = 380 mg/min.
" Water: In euvolemic conditions, 67% of filtered H2O is reabsorbed in PT. Obligatory water loss = 0.4 L/day. Water
permeability is conferred by the presence of water channels (aquaporins) at cell membranes.
o PT: H2O is reabsorbed isosmotically by Standing Osmotic Gradients - continuous reabsorption of Na+ and Cl
-
creates a small increase in the osmolality of the intercellular spaces that drives the reabsorption of water across the
highly water permeable cell membrane and tight junctions.
o D-LOH: D-LOH permeable to water (23%). Driving force for water reabsorption at this segment is the high
osmolality of the medullary interstitium (near 1200mOsm/L).
o TAL: impermeable to water
o Early DT: impermeable to water
o Late DT and CD: Impermeable to H2O in the absence of antidiuretic hormone (ADH) # ADH # water
permeability of these segments ! reabsorption ! excretion of small volume of concentrated urine. Driving force
for reabsorption of water in DT is ! in osmolality between the tubular and interstitial fluids. With low or zero
plasma ADH, permeability to water of late- DT and CD, and there is no reabsorption of H2O ! excretion of a large
volume of dilute urine.
o Aquaporins: AQP1 is present in PT and D-LOH. ADH induces the insertion of AQP2 into late-DT and CD. AQP3
and AQP4 are present at the basolateral membrane of the water permeable tubular segments.
Sodium Regulation: The amount of Na+ in the body determines the volume of the ECF. Volume of the ECF determines perfusion
pressure of the CVS $ [Na+] is critical for proper perfusion of the body.
" Distribution and Balance:
o 40% of total body Na+ is in bone (but fixed ! not available for ordinary metabolic processes)
o 90% of the available Na+ is in the ECF.
o Typical sodium intake ~100 mEq/day (varies from <1mEq/day - 400 mEq/day). Mechanisms that regulate intake are
unclear.
" 1 Eq Na+ = 23 g Na
+ = 58.4 g NaCl).
o Kidneys are the major excretory paths for Na+
-
" stool and sweat losses are negligible (< 10 mEq/day).
o Renal excretion of Na+ is adjusted to match the amount ingested in the diet.
+ excretion in chronic acidosis is highly variable
- usually it is higher than normal).
o Alkalosis (!K+ secretion): upregulating Na
+-K
+ ATPase and # lumenal K
+ permeability.
Diuretics: # solute excretion ! # Cosm above normal
and $ CH20 by raising the osmolarity of the tubular
fluid flowing out of the TAL. Diuretics also # K+
secretion (# rate of tubular flow).
Osmoregulation and Volume Regulation: o Introduction: Volume and concentration of body fluids are controlled by:
o (1) Thirst - Obligatory renal and non-renal water losses would lead to negative water balance if not for thirst.
" Very sensitivy to slight ! osmolality – hyperosmolarity ! stimulation of the hypothalamic thirst center !
water ingestion (returning osmolality to normal).
o (2) Secretion of ADH - modulates urine volume and concentration
" Very sensitivy to slight ! osmolality – hyperosmolality promptly ! secretion of ADH ! $ urine volume
(and # urine concentration).
• without ADH – [urine] = 50mOsm/kg
• with ADH – [urine] = 1200mOsm/kg
o Establishment of Osmotic Stratification (Countercurrent Multiplication of the Single Effect):
o PT: 2/3 of H2O reabsorbed isosmotically (PT reabs. is isosmotic at all levels of plasma osmolality). " PT reabsorption of H2O influences urine concentration by influencing the rate of fluid delivery to the distal
nephron.
o D-LOH and TAL: Osmotic stratification is largely created in ascending limb of the loop of Henle.
" D-LOH: H2O reabsorbed without Na+
" TAL: Na+ reabsorbed without H2O.
o Osmotic equilibration between the interstitium and the D-LOH results in an osmolality difference (osmolality of the ISF and
that in the D-LOH exceeding that of the fluid in the TAL by ~200 mOsm/kg at every level.
o The creation of a 200 mOsm/kg gradient between the lumen of the ascending limb and that of the adjacent descending limb at
each level along its length is termed the single effect and leads to countercurrent multiplication. Multiplication depends on
countercurrent flow whereby tubular fluid moving down the descending limb passes fluid moving upward in the adjacent,
parallel ascending limb.
o Due to osmolality of the interstitum, there is a progressive increase in osmolality as tubular fluid flows downward
toward the hairpin loop and progressive decrease in osmolality as it flows upward, after the turn, through the
ascending limb.
" Osmolality in the lumen of the cortical portion of TAL ~100 mOsm/kg. Osmolality of the
interstitium at the same level is 300 mOsm/kg. Interstitial osmolality progressively rises to ~l200
mOsm/kg from the cortical to the papillary region. Establishment of these gradients permits either
dilution or concentration of the urine, depending on the level of plasma ADH.
• Length of the D-LOH " maximal urine concentration (some animals – not humans – can
adjust loop length to assist osmotic stratification). o Role of Urea: In the inner medulla, urea contributes to osmolality (it is ~50% of solute there). D-LOH is not
permeable to urea. TAL is permeable to urea.
" Antidiuresis (high plasma ADH): ~50% of interstitial osmolality due to urea (~50% due to NaCl).
" Diuresis (low plasma ADH $ low urea reabsorption from the IMCD): significant fraction of filtered urea is
excreted ! contribution to the interstitial osmolality is less important
Transport mechanisms at the TAL that
result in the reabsorption of NaCl. These
mechanisms can maintain an osmotic
difference of 200 mOsm between the lumen
of the TAL and the interstitium (‘single
effect’).
• Urea Transport: markedly ! by ADH; # protein intake ! #urea formation !#urine
incorporation of aquaporins (AQP2) into CD lumenal membranes
ADH: (1) stimulates TAL Na+ transport (#interstitial osmolality ! H2O reabsorption from adjacent CD), (2)
depresses vasa recta blood flow (reduces washout of interstitial solute protecting osmotic stratification) and
(3)enhances IMCD urea transport (urea contributes to interstitial osmolality).
-Higher medullary and papillary interstitial osmolality
(late DT and CD are highly permeable to H2O due to the
presence of ADH) and osmotic equilibration occurs
between the fluid in the CD and the adjacent increasingly
hyperosmotic interstitium.
-The osmolality of the voided urine may be as high as 1200
mOsm/kg with volume as low as 0.4L (obligatory water loss)
o Blood flow through the medulla dissipates the interstitial osmolality gradients.
Counteracted by passive countercurrent exchange of solutes and water between
the closely apposed descending and ascending vasa recta (high permeability to
water and small solutes). Plasma in the descending vasa recta gets concentrated as it
flows into the medulla and diluted in the ascending vasa recta as solutes leave and
water enters the vasa recta (minimizes, but does not abolish, solute washout). o Descending Limb: solutes are concentrated (! permeability to H2O in medulla)
o Ascending Limb: solutes leave vasa recta (! ISF) and H2O enters (solutes are
diluted). Osmolality in A-VR always exceeds that in D-VR at the same level
o NaCl and urea diffuse out of the ascending limb of the vessel and into the descending
limb, while H2O diffuses out of the descending and into the ascending limb of the VR.
Plasma solute
concentration at the end
of the VR is greater
than at the beginning
o Excitatory:
" Osmoreceptors are exquisitely sensitive to the plasma osmolality, # firing when osmolality # ! #ADH.
" Under extreme depletion of both salt and water (or disease states in which volume receptors and
baroreceptors are under-stimulated) ADH secretion # ! renal water reabsorption. (requires a volume
depletion of more than 10%) Under this condition, ADH secretion is stimulated to such an extent that it
overrides the osmoreceptor regulation and can lead to a lowering of osmolality well below normal.
" #Angiotensin II
o Free Water Clearance: amount of water excreted in excess of that which must be excreted in order for urine to be isoosmotic
with respect to plasma and ECF.
Hemorrhage: hemorrhagic shock is defined as the inability to properly perfuse the body. It can be external (penetrating trauma) or
internal (e.g. bleeding peptic ulcer). It may be slow and mild, or rapid and severe.
o Symptoms:
o Skin: pale, cold, and sweaty
o Pulse: tachycardic (rapid) and weak (thready)
o BP: mean arterial pressure is normal or low, and pulse pressure is always low
o Respirations: rapid and shallow
o Kidneys: $urine output (oliguric)
o Causes of Shock: o Hypovolemic shock: caused by $ blood or plasma volume due to loss of fluid through hemorrhage, diarrhea or
vomiting.
o Cardiogenic shock: results from an acute organic impairment of cardiac function such as myocardial infarction o Vasogenic (neurogenic) shock: vasodilation leading to faint and syncope.
" Septic shock: caused by bacterial infections which release toxins that impair CVS " Anaphylactic shock: immunologically-triggered allergic reaction to antigens.
o Immediate Short-Term Reflexes to Hemorrhage ($blood volume):
o ) Blood Volume % ) Venous Pressure % ) Venous Return (PRA)% ) Atrial Pressure % ) Ventricular End
o # recruitment of apical Na+ channels and basolateral Na
+-K
+-ATPase pumps (30-60 minutes latency). # synthesis of
apical Na+ channels and basolateral Na
+-K
+-ATPase pumps (~4-6 hours latency)
• stimulates potassium uptake by cells (preventing hyperkalemia)
• stimulates potassium secretion by principal cells
AII:
• Secretion # by:
o # renin (due to $ ECF)
Functions:
• arteriolar vasoconstrictor
o Low concentrations of AII constrict the efferent arterioles predominantly, and higher concentrations also constrict
afferent arterioles ! $ RBF and GFR.
• stimulates secretion of aldosterone
• stimulates increased thirst
• stimulates secretion of ADH
• stimulates PT Na+ reabsorption (partially mediated by stimulation of Na
+-H
+ exchanger)
ADH:
o Secretion # by: small # plasma osmolality and large (> 10% reductions in ECF volume) and by AII. Inhibitory inputs from
baroreceptors, cardiopulmonary receptors (normal state), and Atrial Natrieuretic Peptide (ANP).
Functions: modulates urine volume and concentration
o induces the insertion of aquaporins into late-DT and CD.
o stimulates Na+ reabsorption by TAL (#interstitial osmolality ! H2O reabsorption from adjacent CD)
o without ADH – [urine] = 50mOsm/kg
o with ADH – [urine] = 1200mOsm/kg
o depresses vasa recta blood flow (reduces washout of interstitial solute protecting osmotic stratification) and o enhances IMCD urea transport (urea contributes to interstitial osmolality).
" Urea Transport: markedly # by ADH; $ protein intake ! $urea formation !$urine concentration; urea
infusion ! prompt # concentrating ability.
Insulin:
• stimulates potassium uptake by cells (stimulates Na+-K
+ ATPase)
Epinephrine:
• Secretion # by $ blood volume (BP)
Functions:
• stimulates potassium uptake by cells
" afferent arteriolar vasoconstriction (via "-1 receptors) ! $RBF and GFR
" stimulation of %-1 receptors in granular cells in afferent and efferent arterioles ! ! renin release.
o Stimulation can be central or in response to # arteriolar perfusion pressure ($ # stretch of afferent arterioles)
Endothelin: vasoconstricts afferent and efferent arterioles (produced by endothelial and mesangial cells).
Nitric oxide: dampens sympathetic and AII activity (produced by endothelial and macula densa cells).
Prostaglandins: released in response to norepinephrine or AII, prevents excessive constrictor responses to these agents.
ATP, Bradykinin, and Histamine: stimulates release of NO.
Dopamine: vasodilator of renal vasculature.
Atrial natriuretic peptide: released upon atrial stretch (! ECF)
Functions:
o dilates afferent arterioles, constricts efferent arterioles and thereby increases GFR.
o # NaCl and water excretion by the kidneys.
" # GFR and Na+.
" inhibits renin secretion by juxtaglomerular cells.
" inhibits aldosterone secretion.
" inhibits (directly) Na+ reabsorption by CD.
" inhibits ADH secretion.
Urodilatin: secreted by DT and CD (acts locally inhibiting Na+ reabsorption by these segments).
NO, Prostanoids, and Kinins: produced in kidneys and inhibit Na+ reabsorption.