Mechanisms which maintain extracellular fluid volume

This chapter vaguely recalls Section I1(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "explain the composition, distribution and movement of body fluids". It is also probably related to the old SectionG5(iv), "explain the humoral regulation of blood volume and flow". The author, bound by his unexplainable attachment to the CICM syllabus document, found it rather difficult to navigate the narrow channel between "humoral regulation of blood volume" and "distribution and movement of body fluids", as both will inevitably involve some of the same physiological systems. 

The main problem of trying to write about this was that the volume of the extracellular fluid is controlled by two parallel and interdependent regulatory pathways: the regulation of body water (by vasopressin and thirst) and the regulation of osmotically active solute in the extracellular fluid (which is mainly sodium, and mainly mediated by the humoral factors like renin angiotensin aldosterone and the natriuretic peptides). Both are necessary for the maintenance of normal extracellular fluid volume and tonicity, and both respond to changes in both volume and tonicity, and also each can activate the other. The problem is that most textbooks divide these into "the defence of volume" and "the defence of tonicity", as if these are somehow completely separate. In defense of this strategy, neurohormonally mediated changes in volume do not necessarily produce changes in tonicity, as the retained fluid should generally be isotonic, whereas changes in tonicity usually do produce changes in volume because they involve the manipulation of water. On this shaky premise, what follows will focus mainly on the defence of volume, leaving discussions of tonicity to the ridiculously apocryphal chapter dealing with the osmoregulatory role of vasopressin.

So as not to reproduce content already available elsewhere in this site, the short summary offered here is linked to relevant pages.

  • The volume of the extracellular fluid is mainly dependent on two factors:
  • Both systems affect each other's function, and are complimentary:
    • Vasopressin-mediated retention of water to restore normal tonicity in a hypertonic state also restores volume, reducing RAAS activity. 
    • RAAS-mediated changes in sodium handing by the kidney produce a reabsorption of sodium, increasing volume and inhibiting vasopressin secretion.
  • Conflict between these systems is resolved in favour of volume:
    • Where the tonicity of the extracellular fluid is low, but the volume is also low, vasopressin secretion is sustained even though it may lead to a decrease in tonicity by the retention of water.

Alternatively, in a sensor-controller-effector matrix beloved by college examiners:

  • Regulation of extracellular fluid tonicity, that can also result in changes to extracellular fluid volume as a byproduct:
    • Stimulus: increase in tonicity of ~ 1%
    • Sensor: the subfornical organ and organum vasculosum lamina terminalis, small circumventricular organs that do not have a blood-brain barrier and are therefore sensitive to changes in tonicity (not osmolality- they seem to deprioritise ineffective osmoles)
    • Afferent: fibres from nucleus of the solitary tract and from abovementioned osmoreceptors 
    • Efferent: vasopressin secretion from the posterior pituitary and binding to renal V2 receptors
    • Effectors: cortical collecting duct cells 
    • Effect: Increased aquaporin expression and increased water permeability of the cortical collecting duct cells, with the result being increased water reabsorption
  • Regulation of extracellular fluid volume:
    • Stimuli: 
      • Decreased intravascular volume: unlike individual cells, which have cytoskeletal tension and membrane stretch-activated mechanisms to detect volume, the extracellular fluid compartment is not equipped with any sensor to help it determine how full it is. However, indirect mechanisms for sensing volume do exist, and they mainly depend on sensing the performance of the cardiovascular system, which is affected by extracellular volume. 
    • Sensors:
      • carotid and aortic baroreceptors (blood pressure)
      • renal medulla (renal perfusion)
      • macula densa (renal sodium delivery)
      • zona glomerulosa of the adrenal glands (sodium concentration, which is affected by extracellular fluid volume changes indirectly, as the result of water retention by vasopressin, the release of which is stimulated by hypotension)
      • Atrial and ventricular mechanoreceptors
    • Afferents:
      • Blood pressure: glossopharyngeal and vagus nerves
      • Renal perfusion: intrinsic renal sensors (which remain to be identified)
      • Sodium: sensors in the macula densa and zoina glomerulosa
    • Efferents:
      • Renin
      • Angiotensin-II
      • Aldosterone
      • Natriuretic peptides
      • Vasopressin
    • Effectors:
      • C​​​​ortical collecting duct cells (vasopressin)
      • Renal tubule (angiotensin, aldosterone, natriuretic peptides)
    • Effects:
      • Sodium retention (angiotensin, aldosterone, natriuretic peptides)
      • Water retention (vasopressin)
      • Restoration of isotonic extracellular fluid
      • Thus, restoration of circulating volume and return of the circulatory system to homeostatic basline conditions.

Why only this abbreviated point form, and not a 10,000-word monograph? Gauer et al (1970) said it best when they started their paper with the words, 

"A complete review of the above topic would be formidable indeed since it would comprise a good part of circulatory physiology, plus the physiology of salt and water balance and, last but not least, the physiology of fluid exchange through cell  membranes."

They went on to complain that they were "encouraged by the editors" to keep their word count to some manageable minimum, and still ended up publishing something that spanned across forty-eight pages of the Annual Reviews of Physiology. Looking at the paper, it seems the authors' error was to reach across fluid physiology into circulatory control (i.e. they expanded on the role of the neurohormonal mechanisms that control blood volume distribution and blood flow), which did critical hubris damage to their word count. 


Gauer, Otto H., JAMES P. Henry, and C. L. A. U. S. Behn. "The regulation of extracellular fluid volume." Annual review of physiology 32.1 (1970): 547-595.