ADRENAL MEDULLA: key player in response to stress

1. ADRENAL MEDULLA: key player in response to stress Consists of modified post-ganglionic sympathetic axons that release predominantly epinephrine (instead of norepinephrine)

2. Adrenal medulla Sympathetic nerves Ach Ach Nicotinic R Chromaffin cell Epi NE

3. STRESS ADRENAL MEDULLA EPINEPHRINE FIGHTOR FLIGHT

4. STRESS? INJURY/DISEASE EMOTION (fear/anxiety) EXERCISE ENVIRONMENTAL (temperature/dehydration) STRESS INDUCES A COORDINATED RESPONSE of Adrenal cortex Adrenal medulla Autonomic nervous system ± involuntary/voluntary behaviors

5. STRESS Adrenal Cortex Symp. NS Adrenal medulla Cortisol NE Epi Secretion of epi stimulated by both preganglionic input and glucococorticoids portal system from cortex to medulla

6. Hypoglycemia causes selective release of EPI, unaccompanied by global changes in sympathetic nerve activity

7. HYPOGLYCEMIA EPI  GLUCAGON  INSULIN GLUCOSE  FFA  KETOACIDS 

8. EPI release regulated by ACTH/cortisol & by preganglionic sympathetic input TROPHISM Cortisol in portal system from cortex Levels of cortisol in medulla are 100X higher than in systemic circulation. Cortisol promotes formation of Epi from NE. RELEASE of EPI Ach  Depolarization  Voltage-activated Ca channels  [Ca2+ ]i  exocytosis

9. 80% of chromaffin cells have portal supply. Receive cortisol; produce epinephrine In Addison’s disease, plasma cortisol is reduced, and plasma epi levels are reduced from 300 to 100 pM. But EPI secretion not physiologically important under unstressed conditions. i.e. Normal plasma EPI level is below physiological threshold 20% of chromaffin cells have no portal supply. No cortisol; produce norepinephrine. But NE secretion not physiologically important. Even under high stress, plasma NE levels are usually sub-threshold

10. .CH.COOH CH 2 TYROSINE NH HO 2 SYNTHESIS tyrosine hydroxylase (rate limiting step) ACTH ACh DOPA DOPAMINE HO CH.CH .NH NOREPINEPHRINE 2 2 HO OH cortisol HO CH.CH .NH.CH EPINEPHRINE 2 3 OH HO

11. NEGATIVE FEEDBACK The catecholamines compete with tyrosine for tyrosine hydroxylase. Release of catecholamines relieves this product inhibition resulting in stimulation of Epi formation

12. H+ countertransport Chromogranin, ATP, Ca2+ H+ countertransport

13. Plasma epi/NE levels ≈ 10–9 M NE rarely reaches physiologically significant levels in plasma. EPI is the important Adrenomedullary hormone Onset and decay of increased plasma EPI levels both rapid; T1/2 ≈ 10sec (response to stress should be rapid and short-lived) 97% EPI/NE broken down to inactive forms by MAO (monoamine oxidase) COMT (catecholamine-O-methyl transferase)

14. NE a = b1 >> b2 Epi a = b1 = b2 Pharmacologically, EPI is like NE, but has additional b2-receptor (metabolic) effects Sympathetic nerve stimulation (NE) and blood EPI are synergistic. There is a lot of overlap in what they do.

15. b2 Vasodilation (muscle) Bronchodilation Lipolysis (b3) Gluconeogenesis and glycogenolysis Glucagon secretion b1 Contractility  Heart rate  Calorigenesis a Vasoconstriction (most places) Pupil dilation Sphincters contract Pilomotor Insulin release  Gluconeogenesis and glycogenolysis

16. METABOLIC EFFECTS OF EPI glucose Ketone bodies glycogen fatty acids glycogen fats glucose-P lactate pyruvate adipose tissue muscle liver Glucagon  Insulin   decreased glucose uptake by muscle & liver

17. ENDOCRINE RESPONSE TO STRESS STRESS SNS ACTH  EPI  CORTISOL  GLUCAGON  INSULIN  GLYCOGENOLYSIS GLUCONEOGENESIS LIPOLYSIS MUSCLE/LIVER GLUCOSE UPTAKE 

18. EPI’s CARDIOVASCULAR EFFECTS HEART HR  Contractility  Venous constriction   Cardiac output   BLOOD VESSELS Contracts arterioles in most tissues (a). Relaxes those in striated muscle and heart (b). Redistribution of blood flow to muscle while maintaining coronary/cerebral flow BLOOD PRESSURE CO  + Ra  Pa 

19. WHAT ELSE? 1) medulla  cortex 2) opioids 3) anti-bacterial peptides “Antibacterial peptides are present in chromaffin cell secretory granules” (lots of them; most derived from chromogranin; released by nerve stimulation) 4) adrenomedullin (hypotensive agent, actions similar to those of ANP, i.e. diuresis and natriuresis)

20. A miniature (backup) hypothalamic/pituitary axis within the adrenal medulla CRH ACTH System up-regulated in hypophysectomized rats cortisol

21. “Adrenal medullary enkephalin-like peptides may mediate opioid stress analgesia” (Lewis et al. Nature 1982) “Opioid stress analgesia” = analgesia induced by stress that is mediated by opioids Analgesia was inhibited by opioid receptor antagonists, and increased by agents that increase medullary opioid levels. “The alleviation of pain by cell transplantation” (chromaffin cells in CNS)

22. SUMMARY 1) Main medullary hormone is epinephrine, key player in the metabolic response to stress. 2) The adrenal medulla is a modified sympathetic ganglion 3) Epinephrine is made from tyrosine, and stored in secretory granules in chromaffin cells. 4) Cortisol stimulates formation of epinephrine, acetylcholine releases it. 5) Epi differs from NE in being a potent b2 receptor agonist. 6) b2 receptors stimulate gycogenolysis, gluconeogenesis, glucagon secretion, and lipolysis. 7) Epi also inhibits insulin production (a effect). 8) The adrenal medulla releases many other compounds. Most may have only paracrine actions, but opioids and adrenomedullin may have systemic effects