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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