Regulation Of Plasma Osmolality And Fluid Volume
Extracellular fluid osmolality must
be closely regulated, as alterations cause the swelling or shrinking of all
cells, and can lead to cell death. The control of osmolality takes precedence
over the control of body fluid volume.
Plasma osmolality is increased in
water deficiency and decreased by the ingestion of water. Osmoreceptors in
the anterior hypothalamus are sensitive to changes as small as 1% of
plasma osmolality, and regulate antidiuretic hormone (ADH), also
known as vasopressin. A rise in osmolality increases ADH release and
stimulates thirst and water reabsorption; a fall has the opposite
effect. ADH is a peptide of nine amino acids formed from a large precursor
synthesized in the hypothalamus (Chapter 44). ADH is transported from
there to the posterior pituitary (neurohypophysis) within nerve
fibres (hypothalamohypophyseal tract), where it is stored in secretory
granules. Action potentials from osmoreceptors cause these to release ADH.
ADH binds to V2 receptors on renal principal cells and increases cyclic
adenosine monophosphate (cAMP), causing the incorporation of water channels (aquaporins)
into the apical membrane (Chapter 34). ADH also causes vasoconstriction (including
renal) via V1 receptors.
The relationship between plasma
osmolality and ADH release is steep
(Fig. 35b), as is the relationship between plasma ADH and urine osmolality
(Fig. 35c). Normal urine production is ∼60 mL/h (urine osmolality, ∼300–800
mosmol/kg H2O. Maximum ADH reduces the urine volume to a minimum of ∼400 mL
per day (maximum urine osmolality, ∼1400 mosmol/kg H2O; this cannot be greater than
that in the deep medulla, Chapter
34). In the absence of ADH, the urine volume can reach ∼25 L per
day with a minimum urine osmolality of ∼60 mosmol/kg H2O (Chapter
34). ADH is rapidly removed from plasma, falling by ∼50% in ∼10 min,
mainly due to metabolism in the liver and kidneys.
Diabetes insipidus is the production of copious amounts of hypo-
tonic (dilute) urine due to defective ADH-dependent water reabsorption.
This may be due to a congenital defect in ADH production (central diabetes
insipidus, CDI), or to a failure to respond to ADH (nephrogenic
diabetes insipidus, NDI) due to defective ADH receptors or
aquaporins.
Control of body fluid volume
(Fig. 35d)
As plasma osmolality is strongly
regulated by the osmoreceptors and ADH, changes in the major osmotic component
of extracellular fluid, i.e. Na+,
will result in changes in extracellular volume. The control of body Na+ content by the kidney is therefore the
main regulator of body fluid volume. Atrial and other low-pressure
(cardiopulmonary) stretch receptors (Fig. 35d) detect a fall in central venous
pressure (CVP), which reflects the blood volume. A fall in volume
sufficient to reduce blood pressure activates the baroreceptor reflex (Chapter
22). In both cases, increased sympathetic discharge causes peripheral vasoconstriction
(increasing total peripheral resistance; TPR),, including vasoconstriction of
the renal afferent arterioles, stimulation of ADH release and
water reabsorption (see above), and release of renin (see below) from granular
cells in the juxtaglomerular apparatus (Chapter 31). Decreased pressure in
the renal afferent arterioles also stimulates renin release, as does reduced
NaCl delivery to the macula densa in the juxtaglomerular apparatus
(Chapter 31) and a reduced glomerular filtration rate (GFR). In extremis, large
falls in blood volume or pressure will promote ADH release and water
retention at the expense of a
decreased plasma osmolality. This only occurs where the alternative is
circulatory failure, and is not sustainable.
Renin, angiotensin and
aldosterone
Renin cleaves plasma angiotensinogen
into angiotensin I, which is converted by angiotensin-converting enzyme (ACE)
on endothelial cells (primarily in the lung) into angiotensin II.
Angiotensin II is the primary hormone for Na+ homeostasis, and has several
important functions (Fig. 35d). It is a potent vasoconstrictor throughout
the vasculature , although in the kidney it preferentially constricts efferent
arterioles, thereby increasing GFR (Chapter 32) and protecting GFR from a fall
in perfusion pressure. It directly increases Na+ reabsorption in
the proximal tubule by stimulating Na+–H+ antiporters; (Chapter 33). It
stimulates the hypothalamus to increase ADH secretion and also causes thirst
. It stimulates the production of aldosterone by the adrenal cortex
. Angiotensin II also tends to potentiate sympathetic activity (positive
feedback) and inhibit renin production by granular cells (negative
feedback). ACE inhibitors are important for the treatment of heart
failure, when the response to reduced blood pressure leads to detrimental fluid
retention and oedema (Chapter 23).
Aldosterone is required for normal Na+ reabsorption and K+ secretion.
It increases the synthesis of transport mechanisms in the distal nephron,
including the Na+ pump, Na+–H+ symporter and K+ and Na+ channels in principal cells, and H+ ATPase in intercalated cells. Na+ reabsorption and K+ and H+ secretion are
thereby enhanced (Chapters 34 and 36). As aldosterone acts via protein
synthesis, it takes hours to have any effect. The production of aldosterone
by the adrenal cortex is directly sensitive to small changes in plasma [K+],
suggesting a primary role for K+ homeostasis.
Atrial natriuretic peptide (ANP; atrial natriuretic factor)
is released from atrial muscle cells in response to stretch caused by increased
blood volume (Chapter 22). ANP inhibits ENaC in principal cells of the distal
nephron (Chapter 34), suppresses the production of renin, aldosterone and ADH,
and causes renal vasodilatation. The net result is increased excretion of water
and Na+.
Diuretics
Osmotic diuretics (e.g. mannitol) cannot be reabsorbed
effectively and, consequently, their concentration in tubular fluid increases
as water is reabsorbed, limiting further water reabsorption. In diabetes
mellitus, high plasma glucose saturates glucose reabsorption (Chapter 33),
resulting in copious amounts of isotonic urine (i.e. same osmolality as plasma)
containing glucose. Diuretic drugs generally inhibit tubular transport
mechanisms. The most potent are loop diuretics (e.g. furosemide), which
inhibit Na+–K+–2Cl− symporters in the thick ascending loop of Henle, thus
preventing the development of high osmolality in the medulla and inhibiting
water reabsorption (Chapter 34). The increased flow (and thus increased K+
secretion), coupled with reduced K+ reabsorption, enhances K+ excretion and can
cause hypokalaemia (low plasma [K+]). Aldosterone antagonists (e.g.
spironolactone) and Na+ channel blockers (e.g. amiloride) reduce
Na+ entry in the distal nephron and inhibit K+ and H+ secretion; they are weak
diuretics, but K+ sparing, and are often given with loop
diuretics to reduce K+ loss. Alcohol
inhibits ADH release, and so
promotes diuresis.
