adrenal gland sympathoadrenal system
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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
Adrenal Gland
  • 3 arterial supply sources
    • Perfuse gland
      • Periph  center
      • Sinusoids
      • Medulla receives blood w/ cortex prod’s
    • Medulla has own arterial supply
slide6
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
slide16
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
slide23

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
slide30
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
slide33
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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