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ADRENAL GLAND; SYMPATHOADRENAL SYSTEM

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

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ADRENAL GLAND; SYMPATHOADRENAL SYSTEM

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  1. ADRENAL GLAND; SYMPATHOADRENAL SYSTEM

  2. Adrenal Gland • 3 arterial supply sources • Perfuse gland • Periph  center • Sinusoids • Medulla receives blood w/ cortex prod’s • Medulla has own arterial supply

  3. 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)

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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)

  9. 3) Dopamine b-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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. Adrenergic Receptors • Heptahelical, G-prot-linked transmembr receptors • 2 categories: a and b, subcategories • a – affinity for adrenaline > noradrenaline • a1 (A, B, D) mostly use Gaq G prot’s • Usually activate PLC ( PKC and DAG and intracell Ca through IP3) • And/or activate PLA2 • a2 (A, B, C) varied • Gai and G0 couple to decr’d activity adenylyl cyclase • Can  act’n K+ channels, inhib’n Ca channels, act’n PLC and/or PLA2 • b – affinity for adrenaline > noradrenaline • All (1, 2, 3) use Gas G prot  act’n ad cyclase

  16. Tissue Receptor Subtype Heart beta1 Adipose tissue beta1beta3? Vascular Smooth Muscle beta2 Airway Smooth Muscle beta2

  17. 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

  18. 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 b3 receptors • More responsive to norepi • Stim’n receptors  enhanced lipolysis  red’n fat stores  decr’d leptin • BUT apparently not mediated through adrenal medulla

  19. 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

  20. 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

  21. 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

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