PL5 Adrenal Medulla and Stress Response

• Adrenal medulla

  during development, postganglionic neurons lost their axons and become secretory cells (chromaffin cell) when stimulated by the preganglionic nerve fibers (via the splanchnic nerves)

  
• Adrenal medulla

  • Constitutes 28% of the mass of adrenal gland
  • Two types of cells: 90% epinephrine-less dense granules, 10% norepinephrine-very dense granules

  
• Adrenal medullary hormones

  Synthesis, release, physiological actions, control of secretion and their metabolism

  
• Synthesis of catecholamines

  Phenylalanine -> Tyrosine -> Dihydroxy phenylalanine (DOPA) -> Dopamine -> Norepinephrine -> Epinephrine
• Deactivation of catecholamines

  Norepinephrine removed by: reuptake into adrenergic nerve endings, diffusion into body fluids and blood, destruction by tissue enzymes (Monoamine oxidase, Catechol-O-Methyl Transferase)
• Excretion of catecholamines

  As free or conjugated metanephrine and normetanephrine (50%), as VMA (35%), small amounts of free norepinephrine and epinephrine
• Alarm or stress response

  1. Increased arterial pressure

  2. Increased blood flow to active muscles, decreased to gastrointestinal tract and kidneys

  3. Increased rates of cellular metabolism

  4. Increased blood glucose concentration

  5. Increased glycolysis in the liver and in muscle

  6. Increased muscle strength

  7. Increased mental activity

  8. Increased rate of blood coagulation

  
• Actions of epinephrine - fight or flight reaction

  Stimulation of the metabolic rate, glycogenolysis in liver and skeletal muscle, mobilization of free fatty acids, increased plasma lactate, increased insulin and glucagon, increased blood pressure and heart rate, dilatation of pupil

  
• Epinephrine - counter regulatory hormone

  Released in response to exercise, hypoglycemia, hypovolemia, exposure to cold, and other emergencies to supply increased energy demands of heart and skeletal muscle while maintaining adequate glucose supply to the brain
• Metabolic actions of epinephrine***

  1. Adipose tissue = Increases hormone sensitive lipase in adipose tissue to increase triglyceride breakdown and release fatty acids. 2. Skeletal muscle = increases glycogenolysis and glucose-PO4 metabolized to ekther CO2 & H2O / released as lactate 3. Liver = increases glycogenolysis in liver to release glucose

  
• Adrenergic receptors

  Alpha receptors (α1, α2), Beta receptors (β1, β2, β3)<|>Norepinephrine excites mainly α receptors, β receptors to lesser extent<|>Epinephrine excites both types of receptors approximately equally

  
• Adrenergic receptor types

  • α1 - ↑ IP3 and Ca++, DAG, sympathetic postsynaptic nerve terminals, ↑ vascular smooth muscle contraction
  • α2 - ↓ cAMP, sympathetic presynaptic nerve terminals, beta cell islets, ↓norepinephrine, ↓ insulin release
  • β1 - ↑ cAMP, heart, ↑ cardiac output
  • β2 - ↑ cAMP, liver, smooth muscle of vasculature, bronchioles, and uterus, ↑ hepatic glucose output, ↓ contraction of blood vessels, bronchioles, and uterus
  • β3 - ↑ cAMP, liver, adipose tissue, ↑hepatic glucose output, ↑lipolysis

  
• Circulatory changes produced in humans by the slow intravenous infusion of epinephrine and norepinephrine

  
• Norepinephrine produces vasoconstriction via α1-receptors, hypertension stimulates the carotid and aortic baroreceptors, producing reflex bradycardia that overrides direct cardioacceleratory effect, consequently, cardiac output per minute falls
• Epinephrine causes a widening of the pulse pressure - because baroreceptor stimulation is insufficient to obscure the direct effect on the heart, cardiac rate and output increase

  
• In skeletal muscle and the liver, the vasodilator effect of epinephrine via β2-receptors usually overbalances the vasoconstrictor effect
• Physiological changes during stress

  • Blood pressure changes
  • Cardiac output changes
  • Peripheral resistance changes
• Vasoconstriction


  Leads to high blood pressure

  
• Vasoconstriction mechanism

  1. EP stimulate β receptor

  2. Bradycardia

  3. Vasoconstriction by α2-adrenergic

  4. Increase BP

  
• Norepinephrine


  Produces vasoconstriction via α1-receptors
• Hypertension


  Stimulates carotid and aortic baroreceptors, producing reflex bradycardia that overrides direct cardioacceleratory effect, consequently, cardiac output per minute falls

  
• Epinephrine


  Causes a widening of the pulse pressure - because baroreceptor stimulation is insufficient to obscure the direct effect on the heart, cardiac rate and output increase

  
• Epinephrine


  Vasodilation in skeletal muscle and the liver via β2-receptors usually overbalances the vasoconstriction produced by epinephrine elsewhere, and the total peripheral resistance drops

  
• Peripheral resistance


  The amount of force exerted on circulating blood by the vasculature of the body
• Adrenal medulla

  • Catecholamine secretion is low in basal states
  • Epinephrine and to a lesser extent norepinephrine is reduced during sleep
  • Certain drugs act directly on the adrenal medulla
  • Physiologic stimuli affect medullary secretion through nervous system in stress
  • Increased adrenal medullary secretion + diffuse sympathetic discharge in emergency situations

  
• Epinephrine


  Secreted from adrenal medulla during stress, in response to sympathetic stimulation

  
• Norepinephrine


  From sympathetic neuron terminals, combined with the circulating epinephrine, prepare the body for stress in several ways

  
• ACTH


  Helps conversion of norepinephrine to epinephrine
• Cortisol


  Stimulates the conversion of norepinephrine to epinephrine by inducing the enzyme phenylethanolamine-N-methyltransferase (PNMT)
• After hypophysectomy (removal of pituitary gland), glucocorticoid concentration falls in blood, epinephrine synthesis is decreased
• In the absence of cortisol, the adrenal medulla secretes norepinephrine

  
• In 21β-hydroxylase deficiency, glucocorticoid secretion is reduced during fetal life and the adrenal medulla is dysplastic (catecholamine level reduced after birth)
• Adrenal medulla secretes

  Norepinephrine and epinephrine stored in granules with ATP and chromogranin A<|>Epinephrine-containing cells also contain/secrete opioid peptides like preproenkephalin, producing circulating metenkephalin<|>Adrenomedullin, a vasodepressor polypeptide

  
• Dopamine

  Injected dopamine produces renal vasodilation, probably by acting on a specific dopaminergic receptor<|>Locally produced in renal cortex, to causes natriuresis

  
• Diseases of adrenal medulla

  • Pheochromocytomas and paragangliomas are catecholamine producing tumors
  • Paragangliomas rarely secrete epinephrine, hypertension is greater with norepinephrine than with epinephrine
  • Tumors are encapsulated; hypertensive crisis is triggered by spontaneous hemorrhages or pressure on the tumor, releasing catecholamines

  
• Diagnosis of pheochromocytoma

  Biochemical testing: Plasma or urine total metanephrines are gold standard screening tools<|>Tumor imaging

  
• Effects of increased plasma cortisol during stress

  • Stimulation of protein catabolism, liver uptake of amino acids, maintenance of plasma glucose levels, stimulation of triglyceride catabolism in adipose tissue
  • Enhanced vascular reactivity (increased vasoconstriction to norepinephrine)
  • Unidentified protective effects against the damaging influences of stress
  • Inhibition of inflammation and specific immune responses
  • Inhibition of non-essential functions (e.g., reproduction and growth)

  
• Other hormones released during stress

  • Beta-endorphin
  • Vasopressin
  • Aldosterone
  • Growth hormone
  • Glucagon

  
• Beta-endorphin


  Co-released with ACTH and may act to reduce pain
• Vasopressin


  Stimulates ACTH secretion and also acts on the kidney to increase water retention