Action Potencial Note

Effect of Diuretics on Potassium Balance

Loop diuretics, that is, diuretics that act primarily on the Na+/K+/2Cl" cotransporter in the thick ascending limb of the loop of Henle, increase the delivery of salt and water to the more distal portions of the nephron because they interfere with Na+ and water reabsorption in the loop of Henle (see also Chapter 28). For the reasons given in the text, the increase in Na+ delivery and volume flow to the connecting tubule and collecting duct favor K+ secretion and excretion, and can lead to a low plasma K+ concentration (hypokalemia) and depletion of total body K+. The thiazide diuretics have a similar effect because they act on the electroneutral NaCl cotransporter in DCT cells, but not on the Na+ channel in the CNT and principal cells. Thus, hypokalemia is a frequent side effect of diuretic therapy. Mild to moderate hypokalemia is associated with muscle weakness, reduced reflexes, and fatigue. When severe, it can lead to coma and fatal cardiac arrhythmias. Patients who are given loop diuretics should be encouraged to eat foods rich in potassium such as fruit juices and bananas, but may still need to take potassium supplements.

In contrast, those diuretics that act on the Na+ channel such as amiloride and triamterene, and spironolactone, which blocks the action of aldos-terone (see next section), are referred to as "potassium-sparing" diuretics because they do not result in increased K+ secretion. Amiloride and triamterene block the Na+ channel in the luminal membrane of principal cells; therefore, they decrease the depolarization of the luminal membrane, resulting in decreased K+ secretion.

Intracellularly, it binds to cytoplasmic and nuclear receptors that are present exclusively in the CNT and principal cells and produces the changes shown schematically in Fig. 7. First, the activity of Na+ channels in the luminal membrane is increased. More Na+ enters the cells, and the transepithelial transport of Na+ rises. The increased luminal membrane Na+ conductance also further depolarizes the luminal membrane and enhances K+ secretion. Second, aldosterone increases the activity and synthesis of Na+,K+-ATPase and it can expand the basolateral membrane surface area by more than twofold. Increases in the activity and number of pumps and the basolateral membrane surface area enhance the ability of the CNT and principal cells to pump Na+ out of the cell and K+ in, again resulting in enhanced Na+ reabsorption and K+ secretion. Third, the hormone increases the synthesis of some of the Krebs cycle enzymes, which increases the ability of the cells to produce ATP and supply energy to the Na+,K+-ATPase. Finally, aldosterone may also increase the activity of K+ channels in the luminal membrane, thus directly stimulating K+ secretion.

The reabsorption of Na+ and secretion of K+ by the distal convolution and collecting duct are not entirely dependent on aldosterone. Even in the complete absence of aldosterone, as in Addison's disease, the kidney excretes a maximum of about 500 mmol of Na+ per day, or about 2% of the filtered load, and 6-8% of the filtered load is still reabsorbed by the distal nephron. At the other extreme, in the presence of maximal aldosterone levels, the kidney excretes less than 0.1% of the filtered load of Na+. Thus, the normal range of regulation of Na+ excretion by aldosterone is 0.1-2% of the filtered Na+ load.

Aldosterone secretion by the adrenal cortex is regulated in the manner of a negative feedback mechanism as described in more detail in Chapter 40. Table 1 lists the normal stimuli for increases and decreases in aldosterone secretion. As might be expected, extracellular fluid (ECF) volume contraction, which is usually the result of a reduction in total body Na+ (see Chapter 29), is a stimulus to increased aldosterone secretion. However, the signal to the adrenal zona glomerulosa cells for the decreased ECF volume is an increase in plasma angiotensin II, which is the most potent stimulus of aldosterone production and secretion (see Chapter 24, the section on the ''Renin-Angiotensin System''). A fall in extracellular fluid volume, a fall in renal arterial pressure, or increased sympathetic outflow to the kidneys increases the release of renin from juxtaglomer-ular cells in the afferent arteriole. Renin leads to an increase in plasma angiotensin II. On the other hand, increases in ECF volume inhibit the release of aldoste-rone. This effect appears to be mediated by the release of atrial natriuretic peptide (ANP) from distended atrial muscle in the heart, which directly inhibits zona glomerulosa cells (see also Chapters 29 and 40).

Small changes in the plasma K+ concentration affect aldosterone secretion. Hyperkalemia stimulates aldosterone secretion, while hypokalemia inhibits it.

Hypokalemia Heart Action Potential

FIGURE 7 Actions of aldosterone on CNT and principal cells in the ARDN. Aldosterone, acting through nuclear receptors, increases the activity of Na+ and K+ channels in the luminal membrane, increases the activity of Na+,K+-ATPase, and increases the synthesis of Krebs cycle enzymes. Spironolactone is a competitive inhibitor of aldosterone binding to its receptor and thus acts as a diuretic by antagonizing the action of this hormone.

FIGURE 7 Actions of aldosterone on CNT and principal cells in the ARDN. Aldosterone, acting through nuclear receptors, increases the activity of Na+ and K+ channels in the luminal membrane, increases the activity of Na+,K+-ATPase, and increases the synthesis of Krebs cycle enzymes. Spironolactone is a competitive inhibitor of aldosterone binding to its receptor and thus acts as a diuretic by antagonizing the action of this hormone.

Again, this is a logical negative feedback mechanism because aldosterone release counteracts hyperkalemia by increasing K+ secretion by the CNT and principal cells. Aldosterone release from the adrenal cortex is also increased by some less specific stimuli such as trauma, stress, fright, and general sympathetic discharge. In contrast with its role in regulating the glucocorticoids, adrenocorticotropic hormone (ACTH) has little effect on aldosterone secretion. Nevertheless, ACTH weakly

TABLE 1 Factors That Alter Aldosterone Secretion by the Zona Glomerulosa Cells of the Adrenal Cortex

Increased aldosterone secretion Decreased aldosterone secretion

" Plasma angiotensin II (via angiotensin II receptors on zona glomerulosa cells) # ECF volume, # cardiac output, or functional hypovolemia; see Clinical Note (primarily via the renin-angiotensin system) " Plasma K+ (direct effect on zona glomerulosa cells) Trauma, stress (via generalized sympathetic discharge?)

I Plasma angiotensin II

" ECF volume (via suppression of the renin-angiotensin system, and the release of ANP from the atria)

# Plasma ACTH (loss of a small trophic effect on zona glomerulosa cells?)

stimulates aldosterone release, and aldosterone secretion is diminished when plasma ACTH levels are decreased. Interestingly, glucocorticoids also stimulate K+ secretion but, in contrast to the mineralocorticoid aldosterone, this effect is indirect. Glucocorticoids enhance glomerular filtration and thus augment the delivery of Na+ and fluid to principal cells in the distal nephron, which, as discussed earlier, increases K+ secretion.

As discussed in Chapter 40, the aldosterone receptors in CNT and principal cells can be activated by the glucocorticoid cortisol almost as well as by aldosterone. Because the plasma levels of cortisol are usually several-fold higher than those of aldosterone and exhibit large diurnal variations, the aldosterone signal would be drowned out if it were not for the presence of the enzyme 11 ^-hydroxysteroid dehydrogenase, which converts cortisol to cortisone, a steroid that does not bind to the mineralocorticoid receptor. Only the CNT and principal cells in the nephron express this enzyme, but it is found in other epithelia that are regulated by aldosterone (e.g., the colonic epithelium and sweat ducts), and it is responsible for the selective response of these cells to aldosterone and not to cortisol.

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