ADRENAL GLAND; SYMPATHOADRENAL SYSTEM. Adrenal Gland 3 arterial supply sources –Perfuse gland Periph center Sinusoids Medulla receives blood w/ cortex.

ADRENAL GLAND; SYMPATHOADRENAL SYSTEM

Adrenal Gland

• 3 arterial supply sources – Perfuse gland

• Periph center • Sinusoids• Medulla receives blood w/ cortex prod’s

– Medulla has own arterial supply

• Medulla, cortex diff embryo origins– Cortex from posterior abdominal wall lining– Medullary pheochromocytes from

sympathogonia• Neural crest cells• Also give rise to neuroblasts; sympathetic

ganglia

• SF-1 req’d for adrenal gland dev’t– Also gonads, ventromedial nucleus of

hypothal– Also DAX-1 req’d

• During dev’t, pheochromoblasts migrate to other areas (aorta, organ of Zuckerkandl)

Adrenal Cortex • Produces steroid hormones • Cholesterol-processing enz’s in sER, inner

mitoch membr– Tubulovesicular mitoch

• Much inner membr surface area • Much P450scc

• Parenchymal cells can produce cholesterol de novo– Mainly endocytosis of LDL– Cholesterol-rich lipid droplets in cytoplasm

• Capsule + 3 cell layers

Adrenal Medulla • Mod’d sympathetic ganglion

– BUT no axons at targets– Release catecholamines to ECF bloodstream

• Cells = pheochromocytes– Axonless secr cells– Two cell subpopulations

• Same cell pop’n under diff physiologic states– Concent cortisol exposure

• Noradrenaline (norepinephrine) producing cells• Adrenaline (epinephrine) producing cells

– Secrete prod’s from granules ECF by exocytosis

Catecholamines

• Synth’d from L-tyrosine• Dopamine, noradrenaline, adrenaline• L-tyr in plasma (1-1.5 mg/dL)• Active transport into cells• Conversion L-tyr by 4 enz’s

– Compartmentalized

• Adrenal medulla catecholamine output approx 80% adrenaline– BUT plasma ratio 9:1 noradrenaline:

adrenaline

1) Tyrosine Hydroxylase

Ring hydroxylation to L-DOPA (L-Dihydroxy-PhenylAlanine)

• Contains Fe+2; tetrahydrobiopterin cofactor• Activity reg’d by preganglionic nerves

– Get phosph’n PKA, PKC and calmodulin-dependent kinases

• Long-term stim’n upreg’n transcription, translation

• Incr’d L-DOPA prod inhib’n

2) DOPA Decarboxylase (aromatic L-amino acid decarboxylase)

• Pyridoxal phosphate cofactor

• End product in CNS

• Stored in secretory vesicles– Enter by active transport– MVATs (Vesicular MonoAmine Transporters)

3) Dopamine -Hydroxylase (DBH)

side chain hydroxylation to noradrenaline

• Contains Cu; Vit C cofactor

• Rxn w/in secretory vesicle

• End prod in symp nerves, most central catecholaminergic neural tracts

4) Phenylethanolamine N-MethylTransferase (PNMT)

N-methylation to adrenaline

• Methyl donor = S-AdenosylMethionine

• Cytoplasmic– Noradrenaline leaves vesicle

• Passive transport • Concent gradient

– Adrenaline must reenter secretory vesicle • Active transport

PNMT

• Expression depends on high local cortisol – From adrenal cortex– Through sinusoid system

• Transcr’l activation of PNMT gene through ligand-act’d glucocort receptor– Also other transcription factors

• Also activity stim’d by glucocort • Adrenaline prod feedback inhib’n• Also found in kidney, lung, pancreas• Also nonspecific NMT

– Contributes to periph conversion norepi to epi

Secretory Vesicles

• Catecholamine storage

• Active transport via VMATs– ATP-driven proton pump – In vesicle membranes– pH, electrical gradient– Antiporter

• 12 transmembr helical segments– Related to plasma membr monoamine

transporters

Catecholamine Release from Storage Vesicles

• ACh rel’d from preganglionic fibers Nicotinic receptors– Get depol’n pheochromocytes act’n voltage-gated Ca channels influx Ca exocytosis of secretory vesicles

• Chromogranins, DBH, ATP, other peptides released

Actions of Catecholamines

• Circ’ng catecholamines reach most tissues– BUT cannot penetrate

• BBB• Fetus

– Fetal prod’n (mostly norepi) through fetal zone• Impt in intrauterine life (cardiovascular responses)• Large • Placenta expresses catecholamine degrading enzymes

• Placental norepi transporter – Delivers circ’ng fetal chatechol’s for degrad’n

Adrenergic Receptors

• Heptahelical, G-prot-linked transmembr receptors• 2 categories: and , subcategories – affinity for adrenaline > noradrenaline

1 (A, B, D) mostly use Gq G prot’s• Usually activate PLC ( PKC and DAG and intracell Ca through IP3)• And/or activate PLA2

2 (A, B, C) varied• Gi and G0 couple to decr’d activity adenylyl cyclase• Can act’n K+ channels, inhib’n Ca channels, act’n PLC and/or

PLA2

– affinity for adrenaline > noradrenaline• All (1, 2, 3) use Gs G prot act’n ad cyclase

Tissue Receptor Subtype

Heart beta1

Adipose tissue beta1beta3?

Vascular Smooth Muscle beta2

Airway Smooth Muscle beta2

Physiological Implications of Sympathoadrenal Catecholamines

• Gen’l: activates fight/flight mech’s– Mobilizes energy, redist’s blood

• Opposes parasymp – Promotes digestion, storage of energy– BUT distinct target cell pop’ns w/in organs

• Many targets; overall– Incr’s cardiac output, blood pressure– Bronchodilation matched perfusion w/ incr’d ventilation– Blood diverted from viscera and skin to muscle

• Retain blood to brain

– Mobilize fuel from energy stores

• Stress sympathoadrenergic, adrenocortical systems activated simultaneously– Catecholamines instantaneous action

• From adrenal medulla and symp neurons• Rapid elimin’n w/ end release

– Cortisol delayed 20-30 mins, action prolonged

• Involved in body weight regulation– Leptin secr’d by adipocytes

• Acts on hypothal decr’d appetite, incr’d energy expenditure

– Adipocytes have 3 receptors• More responsive to norepi

– Stim’n receptors enhanced lipolysis red’n fat stores decr’d leptin

• BUT apparently not mediated through adrenal medulla

Dopamine

• Five receptor types– All G-prot coupled heptahelical– D1 stim’s adenylyl cyclase

vasodilation in splachnic region

– D2 inhibits adenylyl cyclase

• Impt: antihypertensive, natriuretic through autocrine/paracrine mech’s– Opposes aldosterone

Catecholamine Elimination

• Short-lived mol’s – 10 sec to 1.7 min

• 50-60% assoc’d w/ albumin• Elimin’n

– At synapse, ISF near symp neurons• Reuptake into nerve terminals• Reenter vesicles via VMAT OR• Become degraded by MAO

– In target cells• Degraded by Catechol-O-MethylTransferase (COMT)

– 5% directly filtered into urine

• MAO– In outer mitoch membr– Substr’s also serotonin, histamine– Oxidizes amino grp aldehydes– Further ox’d by nonspecific aldehyde deHase– Ultimate prod dihydroxymandelic acid (DOMA)

• COMT – extraneuronal degradation– Uses SAM as methyl donor– Impt to circ’g catecholamines

• Get final conjugation– Sulfate, glucuronate in liver, gut – Excr’n through urine