Viva G5(iv)

This viva tests Section G5(iv) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "explain the humoral regulation of blood volume and flow".

What are these "humoral" systems which regulate volume and flow?
  • These are regulatory feedback mechanisms which use circulating hormones to make ajustments to circulatory parameters
  • The goal is to maintain a stable intravascular volume, stable blood pressure, stable osmolality and serum sodium content (as it influences extracellular fluid volume)
  • These systems involve the nervous system usually as sensors, and use the endocrine system as effectors. 
  • End targets are vascular smooth muscle, renal tubule channels and behavioural triggers (eg. increased thirst)
Which such neurohormonal systems are you aware of?
  • Sympathetic-adrenal system
  • Renin-angiotensin-aldosterone system
  • Vasopressin
How does the sympathetic nervous system regulate blood flow?
  • Stimulus: hypotension, hypovolemia, hypoglycaemia
  • Sensor: various baroreceptors in the carotid sinus, aorta and atria, as well as descending input from the cortex (eg. some emotional trigger for a fight-or-flight response)
  • Afferent: glossopharyngeal and vagus nerves, thalami, cerebral cortex
  • Efferent: sympathetic nervous system, descending from the rostral ventrolateral medulla via the intermediolateral column of the spinal cord. Specifically, the adrenal glands are innervated by the greater splanchnic nerve, which supplies fibres from T5-T9  to the coeliac plexus. Preganglionic T7-T9 fibres project to the chromaffin cells of the medulla, and these are cholinergic fibres (Parker, 1993)
  • Effector: Adrenal chromaffin cells, modified nerve endings which secrete catecholamines (adrenaline and noradrenaline) directly into the circulation
    • There is usually more noradrenaline than adrenaline
  • Effect: vasoconstriction of peripheral circulation (particularly cutaneous),  vasodilation of some muscle vascular beds, redistribution of splanchnic blood flow
How does the sympathetic nervous system regulate blood volume?
  • Directly, by the regulation of sodium reabsorption via the renal tubule
    • Sodium reabsorption in the proximal tubule, which appears to be an alpha-1 effect (Biaggioni et al, 2007)
    • Changing the vascular resistance in the afferent and efferent arterioles, therefore altering the glomerular filtration rate
  • Indirectly, by affecting the renin-angiotensin-aldosterone system
    • renin release is stimulated by beta-1 effects
  • Indirectly, by stimulating the release of EPO and therefore increasing the cellular volume of the blood
What the hell is this "renin"?
  • Renin is a large-ish 37 kDa enzyme which is synthesised by juxtaglomerular cells of the renal cortex (Persson, 2003).
  • It is produced by cutting chunks out of prorenin, a slightly larger precursor protein (46kDa). This substrate is present in the blood at relatively high concentrations, around 1.3mg/L.
  • Renin remains in storage vesicles of the juxtaglomerular cells, waiting to be released by a range of stimuli (which will be discussed below).
  • Its release and serum concentration level is the rate-limiting step in the pathway of RAAS activation
What stimulates renin secretion?
  • Systemic hypotension:
    • Baroreceptor responses to low blood pressure
    • This stimulates the sympathetic nervous system, which in turn stimulates the juxtaglomerular cells. 
    • There are β-1 receptors on the juxtaglomerular cells, which respond to direct adrenergic innervation as well as circulating catecholamines.
    • Then, via increasing intracellular cAMP, protein kinase A mediates the degranulation of renin-containing cells.
    • In fact, anything that ends up increasing cAMP (prostaglandin I2 and E2, milrinone, theophylline) will also produce this effect.
  • Renal hypoperfusion
    • Mechanism is unclear
    • a MAP of about 85 is roughly the threshold for renin release:
  • Salt depletion
    • Decreased salt intake produces the release of renin, and vice versa.
    • The macula densa is implicated, as well as several other renal vascular and parenchymal regions. 
What other factors affect renin release?
  • ANP secretion (promotes natriuresis rather than sodium retention)
  • Endothelin (increases blood pressure)
  • Angiotensin II (negative feedback mechanism)
  • Increased blood flow to the juxtaglomerular cells (decreases renin release)
Explain how the RAAS amplifies the renin release as a signal
  • Angiotensinogen is the substrate for renin, and gets cleaved
  • Angiotensin-I is an inert decapeptide, and a substrate for ACE
    • ACE also involved in the degradation of bradykinin, so...
  • Angiotensin-II is produced from angiotensin-I by ACE. it is an octapeptide

extremely simplified diagram of RAAS

What are the pharmacokinetics of angiotensin II?
  • A short-lived molecule,
  • Degraded rapidly by endothelial angiotensinases
  • Halflife of around 30 seconds
What are the physiological effects of angiotensin II?
  •  Vasoconstrictor: twice as potent as noradrenaline:
  • Stimulating the release of vasopressin
  • Stimulating the release of aldosterone
  • Increased Na+/H+ exchange in the proximal tubules, thus sodium retention and acid excretion
  • Increased sensation of thirst
  • Increased sensitivity to catecholamines
Describe the activity of angiotensin receptors
  • These are membrane surface receptors
  • AT1 and AT2 forms are well characterised
  • They are G-protein coupled receptors
  • AT1 are Gq/11 and Gi/o whereas  AT2 are Gi2 and Gi3 
  • AT1 activate phospholipase C and increase intracellular calcium, producing all kinds of vasoconstrictor effects; these are the clinically relevant receptors for haemodynamics
  • AT2 are mostly involved in LV remodelling and vascular growth
What stimulates aldosterone release?
  • Steroid hormone produced by the adrenal zona glomerulosa
    • Angiotensin II release
    • High serum potassium
    • Direct effect of the adrenocorticotropic hormone (ACTH)
  • The zona glomerulosa is the "sensor" organ for aldosterone release.
    • This is mediated by the A1 angiotensin receptor on the surface of zona glomerulosa cells,  which is a G-protein coupled receptor.
    • Potassium is directly sensed by these cells:
      • Zona glomerulosa cells are highly sensitive to changes in potassium concentration mainly because they have highly conductive membrane potassium channels
      • If the potassium concentration changes even slightly, the membrane potential also changes, the calcium channels open, and calcium enters the cells where it can act as a second messenger molecule to mediate aldosterone synthesis. 
What are the physiological effects of aldosterone?
  • Increased sodium resorption
  • Increased potassium elimination


  • Aldosterone interacts with a mineralocorticoid receptor in the cells of the distal tubule and increases the expression of a luminal sodium channel which then promotes the reabsorption of sodium and the excretion of potassium.
  • It does something similar in the colon, increasing the reclamation of sodium from the stool.
  • The timeframe of these changes is over the course of days

Also involves modifications of behaviour, hunger, thirst, and baroreceptor function.

Also all sorts of unpleasant cardiovascular remodelling and inflammatory changes.

How is vasopressin involved in the regulation of blood flow and blood volume?

Nonapeptide secreted by the posterior pituitary.

The stimuli for vasopressin release are hypotension and hyperosmolarity.

  • Hypotension is sensed by arterial baroreceptors in the usual way, and when the nucleus of the solitary tract is responding to this stimulus, one of its efferent projections extends to the hypothalamus to stimulate vasopressin release.
  • Hyperosmolarity is sensed by hypothalamic subfornical organ and the organum vasculosum of the lamina terminalis, thankfully abbreviated as OVLT

V2 receptors:

  • at the cortical collecting duct
  • stimulate the increased expression of aquaporin proteins on the surface of the collecting duct
  • Thus, increased water reabsorption

V1 receptors:

  • Widespread through the systemic arterial circulation
  • G-protein coupled, and binding to them activates phospholipase-β which produces IP 3 and leads to the predictable increase in intracellular calcium 
  • Responsible for the vasopressor response
How is vasopressin used as a vasopressor?
  • In shock, there is a relative vasopressin deficiency, and the receptors are all unoccupied (whereas all the other vasopressors are saturating their receptors)
  •  Vasopressin potentiates the effects of noradrenaline, which is present in vast concentrations in a shocked patient, but only in minimal concentrations in a healthy euvolaemic patient.
  • Vasopressin directly inactivates KATP channels in vascular smooth muscle, which is extensively activated in sepsis and which contributes significantly to the vasoplegia (Buckley et al, 2006), but which is fairly quiescent in health.
  • Vasopressin decreases the synthesis of inducible nitric oxide synthase that is stimulated by bacterial lipopolysaccharide and inflammatory cytokines, which leads to the recovery of vessel tone. 
  • In healthy patients,  the cardiovascular effects of vasopressin appear to be completely unrelated to its dose


Biaggioni, Italo. "The sympathetic nervous system and blood volume regulation: lessons from autonomic failure patients." The American journal of the medical sciences 334.1 (2007): 61-64.