Endocrine

Question 1

Outline the physiology of the adrenal gland (70% of marks). Describe the actions of aldosterone (30% of marks).

Past question

Answer 1

The adrenal cortex:
	- Consists of 3 distinct zones (Mnemonic Go Find Rex, Make Good Sex)
		○ Zona glomerulosa - mineralocorticoids (aldosterone). Also responsible for regeneration of cortical cells
		○ Zona fasciculata - glucocorticoids (cortisol)
		○ Zona reticularis - sex hormones (DHEA)
	- The above hormones are produced on demand, rather than stored in the adrenal gland
	- All adrenocortical hormones are synthesised from cholesterol:

The adrenal medulla:
	- Derived from neural crest tissue and functionally an analogue of sympathetic postganglionic fibres of the autonomic nervous system
	- Innervated by long sympathetic preganglionic cholinergic neurons (T5-T9)
	- 2 types of chromaffin cells
		○ ~80% have large and less dense granules containing adrenaline
		○ ~20% have small and dense granules containing noradrenaline
	- Control of catecholamine secretion:
		○ Stimulated by release of acetylcholine from preganglionic sympathetic nerve fibres in greater splanchnic nerve
		○ Depolarisation of chromaffin cells --> calcium influx --> exocytosis & release of catecholamines
		○ Angiotensin II also potentiates the release of catecholamines
		○ PNMT catalyses the formation of noradrenaline to adrenaline, and is only found in the adrenal medulla and brain

Aldosterone
- C21 corticosteroid - major mineralocorticoid produced by zona glomerulosa
- Half life of 20min and transported mainly by plasma albumin and corticosteroid-binding globulin (10%)
- 90% is inactivated by single pass through liver - reduction of the double bond of the A ring of the steroid structure. Tetrahydroaldosterone is formed and conjugated with glucuronide and excreted readily by the kidney
- Physiological effects:
○ Renal
§ Binds to intracellular mineralocorticoid receptors in the principal cells of DCT & CDs –> increased Na+ absorption and potassium excretion
□ Increases Na+ entry at apical membrane through amiloride-sensitive epithelial Na+ channel
§ Induces DNA transcription, producing proteins that increase Na+/K+ ATPase in the basolateral membrane of the kidney, colon and bladder cells
§ Increases the expression of H+-ATPase in apical membrane and Cl/HCO3 exchanger in the basolateral membrane of intercalated cells
§ Increases the number of K+ channels in the apical membrane of DCT cells (enhances K+ secretion) & in GI mucosa
○ Extra renal
§ Promotes Na+ reabsorption in sweat glands, salivary glands and GI mucosa of the distal colon
- Control of secretion:
○ Aldosterone is controlled by 3 well defined mechanisms
§ ACTH - enhances aldosterone synthesis by catalysing the conversion of cholesterol to pregnenolone
§ Serum K+ - 1% increase in plasma K+ can promote the release of aldosterone from the zona glomerulosa (probably due to depolarisation of zona glomerulosa cell membrane)
§ Renin-angiotensin system
□ Renin is released by juxtaglomerular cells in response to a decrease in effective circulating blood volume due to acute hypovolaemia or hypotension
□ Renin combines with angiotensinogen (a2 globulin) to produce angiotensin I, an inactive decapeptide. Angiotensin I is then converted to Angiotensin II by ACE
□ Angiotensin II has a half life of 1-3min, and stimulates the secretion and synthesis of aldosterone by the zona glomerulosa

Question 2

Describe the physiology of the Renin and Angiotensin system.

Answer 2

Stimulus: hypotension, hypovolemia, salt depletion, renal hypoperfusion
Sensor:
- arterial and renal baroreceptors
- β-1 receptors on the juxtaglomerular cells
Afferent: glossopharyngeal and vagus nerves, renal sensors (macula densa)
Efferent: enzymatic steps:
- Renin
○ 37 kDa enzyme with half life 40-120min
○ Released from juxtaglomerular (granular) cells in juxtaglomerular apparatus
○ Is the rate-limiting step
○ Cleaves angiotensiongen into angiotensin-I
- ACE
○ Pulmonary enzyme which cleaves angiotensin-I into angiotensin-II
- Angiotensin-II
○ Increases Na+/H+ exchange in the proximal tubules, thus sodium retention and acid excretion
○ Increases sensation of thirst
○ Increases sensitivity to catecholamines
○ Stimulates the release of vasopressin
○ Stimulates the release of aldosterone
○ Decreases the sensitivity of the baroreceptor reflex (by binding to AT1 receptors in NTS)
○ Degraded to angiotensin III by angiotensinases (blood/tissue peptidases)
- Vasopressin and aldosterone
○ Produce more vasoconstriction as well as more salt and water retention
Effectors:
- A2 receptors, adrenal glomerulosa, pituitary gland, renal tubule
Effect: vasoconstriction of peripheral circulation and the increase in body fluid volume (via Na+ & H2O retention)
Regulation: primarily regulated by renin release, which in turn is regulated by tubular Na+ delivery, negative feedback from angiotensin II, renal blood flow