Physiology Of The Mineralocorticoids

Although several naturally occurring adrenal cortical hormones, including glucocorticoids, can produce mineralocorticoid effects, aldosterone is by far the most important mineralocorticoid physiologically. In its absence there is a progressive loss of sodium by the kidney, which results secondarily in a loss of extracellular fluid (see Chapter 29). Recall that the kidney adjusts the composition of the extracellular fluid by processes that involve formation of an ultrafiltrate of plasma followed by secretion or selective reabsorption of solutes and water. With severe loss of blood volume (hypovolemia), water is retained in an effort to restore volume, and the concentration of sodium in blood plasma may gradually fall (hyponatremia) from the normal value of 140 mEq/liter to 120 mEq/liter or even lower in extreme cases. With the decrease in concentration of sodium, the principal cation of extracellular fluid, there is a net transfer of water from extracellular to intracellular space, further aggravating hypovolemia. Diarrhea is frequently seen and it, too, worsens hypo-volemia. Loss of plasma volume increases the hema-tocrit and the viscosity of blood (hemoconcentration). Simultaneous with the loss of sodium, the ability to excrete potassium is impaired, and with continued dietary intake, plasma concentrations of potassium may increase from the normal value of 4 mEq/liter to 8-10 mEq/liter (hyperkalemia). Increased concentrations of potassium in blood, and therefore in extracellular fluid, result in partial depolarization of plasma membranes of all cells, leading to cardiac arrhythmia and weakness of muscles including the heart. Blood pressure falls from the combined effects of decreased vascular volume, decreased cardiac contractility, and decreased responsiveness of vascular smooth muscle to vasoconstrictor agents caused by hyponatremia. Mild acidosis is seen with mineralocorticoid deficiency, partly as a result of deranged potassium balance and partly from lack of the direct effects of aldosterone on hydrogen ion excretion.

All of these life-threatening changes can be reversed by administration of aldosterone and can be traced to the ability of aldosterone to promote inward transport of sodium across epithelial cells of kidney tubules and the outward transport of potassium and hydrogen ions into the urine. It has been estimated that aldosterone is required for the reabsorption of only about 2% of the sodium filtered at the renal glomeruli; even in its absence, about 98% of the filtered sodium is reabsorbed. However, 2% of the sodium filtered each day corresponds to the amount present in about 3.5 L of extracellular fluid. Aldosterone also promotes sodium and potassium transport by the sweat glands, the colon,

Physiology of the Mineralocorticoids and the salivary glands. Of these target tissues, the kidney is by far the most important.

Effects of Aldosterone on the Kidney

Initial insights into the action of aldosterone on the kidney were obtained from observations of the effects of hormone deprivation or administration on the composition of the urine. Mineralocorticoids decrease the ratio of urinary sodium to potassium concentrations; in the absence of mineralocorticoids, the ratio increases. However, although aldosterone promotes both sodium conservation and potassium excretion, the two effects are not tightly coupled, and sodium is not simply exchanged for potassium. Indeed, the same amount of aldosterone that increased both sodium retention and potassium excretion when given to adrenalectomized dogs stimulated only potassium excretion in normal, sodium-replete dogs. Similarly, when normal human subjects were given aldosterone for 25 days, the sodium-retaining effects lasted only for the first 15 days, but increased excretion of potassium persisted for as long as the hormone was given (Fig. 9). Renal handling of sodium and potassium is complex, and compensatory mechanisms exerted at aldosterone insensitive loci within the kidney can offset sustained effects of aldosterone on sodium absorption when measured in the otherwise normal subject.

Renal tubular epithelial cells are polarized. Permeability properties of the membrane that faces the lumen are different from those of the basolateral membranes that face the interstitium. Reabsorption of sodium depends on entry through channels in the luminal membrane followed by extrusion by the sodium-potassium-dependent ATPase in the basolat-eral membranes. This enzyme is energized by cleavage of ATP and exchanges three sodium ions for two potassium ions. Potassium, which would otherwise accumulate within the cells, can then passively diffuse through channels located in both the luminal and basolateral membranes (Fig. 10). Consequently, movement of sodium from the lumen to the interstitium is not necessarily accompanied by equivalent movement of potassium in the opposite direction. The proportion of potassium that back-diffuses into the interstitium depends on the relative strengths of the electrochemical gradients across the luminal and basolateral


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