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+.
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.