Question 8

College Answer

Better answers for this question used the “sensor, integrator/controller, effector” structure. They also included appropriate detail relating to the site and mechanism of angiotensin II and the subsequent stimulation of ADH and aldosterone release. A detailed description of ADH was necessary to score well. Lengthy descriptions of body water distribution or renal handling of water did not attract additional marks. Answers that scored less well were often disorganised, with limited structure and incorrect facts.

Discussion

The stem of this question is identical to Question 1 from the second paper of 2021, but the college comments are sufficiently different that one might think the marking criteria must have changed from paper to paper. In 2021, there was no mention of "site and mechanism of angiotensin II and the subsequent stimulation of ADH and aldosterone release". The pass rate has increased from 28% to 42%, suggesting that some of the candidates have been looking at the past papers.

Extracellular tonicity is the sensed variable.

• The normal value is about 285 mOsm/kg
• Tonicity is the main determinant ( ineffective osmoles are less stimulating)

Hypothalamic osmoreceptors are the sensors

• Located in the organum vasculosum lamina terminalis (OVLT) and the subfornical organ
• These are circumventricular organs and lack a blood-brain barrier
• These are mechanoreceptors which change their firing rate in response to osmotic swelling or shrinking

Afferent signal is via OVLT and subfornical organ nerves fibres to the hypothalamus

Another mechanism of stimulating the same system is via hypotension

• The sensed variable (blood pressure) is measured by the carotid baroreceptors
• Afferents are the carotid sinus nerve (branch of the glossopharyngeal)

Central controller/integrator is the hypothalamus

• Specifically, the hypothalamic supraoptic nucleus and periventricular nucleus
• There, the vasopressin-producing magnocellular neuron cell bodies reside

Efferent signal is vasopressin

• Vasopressin is released from nerve terminals in the posterior pituitary
• Vasopressin secretion is minimal below an osmolality of 285 mOsm/kg,
• At normal euvolemia, usually the plasma level is 3 pmol/L
• It increases markedly (twentyfold) when extracellular tonicity increases
• It increases massively (a thousand fold) in the presence of hypotension

Effector organ is the renal collecting duct

• V2 receptor binding leads to expression of apical aquaporins
• This increases the water permeability of the collecting duct cells

Effect on urine concentration

• Range is from 1200-1400 mOsm/kg to 40-50 mOsm/kg
• Maximal response occurs at a vasopressin concentration of about 5 pmol/L, corresponding to an extracellular fluid osmolality of around 290 mOsm/kg

Another effector mechanism is thirst

• Hypothalamic neurons project to the anterior cingulate gyrus and mediate thirst sensation as well as behavioural changes (drinking, water-seeking)

Indirectly, total body water is also affected through sodium regulation by:

• Renin-angiotensin system
  • Angiotensin II increases Na⁺/H⁺ exchange in the proximal tubules, thus sodium retention, and thus water retention
  • It also stimulates the release of vasopressin and increases the sensation of thirst
• Aldosterone
  • Release is stimulated by angiotensin II
  • Aldosterone interacts with a mineralocorticoid receptor in the cells of the distal tubule and increases the expression of a luminal sodium channel (eNAC) which then promotes the reabsorption of sodium, and therefore of water
• Natriuretic peptides
  • Decreased ANP and BNP secretion resulting from decreased atrial stretch increases the retention of sodium and water 

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