Adrenal gland sympathoadrenal system
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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

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ADRENAL GLAND; SYMPATHOADRENAL SYSTEM

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Adrenal gland sympathoadrenal system

ADRENAL GLAND; SYMPATHOADRENAL SYSTEM


Adrenal gland

Adrenal Gland

  • 3 arterial supply sources

    • Perfuse gland

      • Periph  center

      • Sinusoids

      • Medulla receives blood w/ cortex prod’s

    • Medulla has own arterial supply


Adrenal gland sympathoadrenal system

  • 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

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

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

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

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

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 b hydroxylase dbh

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


4 phenylethanolamine n methyltransferase pnmt

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


Adrenal gland sympathoadrenal system

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

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

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

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

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


Adrenal gland sympathoadrenal system

Tissue

Receptor Subtype

Heart

beta1

Adipose tissue

beta1beta3?

Vascular Smooth Muscle

beta2

Airway Smooth Muscle

beta2


Physiological implications of sympathoadrenal catecholamines

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


Adrenal gland sympathoadrenal system

  • 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


Dopamine

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

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


Adrenal gland sympathoadrenal system

  • 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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