Immediate Adaptations

About 25 mol of sodium are filtered every day by the kidneys in a normal human. Because dietary salt intake on a Western diet is typically 130-260 mmol daily, approximately 3 pounds of salt (17 mol = 1 kg NaCl) must be reabsorbed every day by the renal tubules to maintain salt balance. All sodium chloride reabsorption along the mammalian nephron is driven by the action of Na/K ATPase, which is present along the basolateral cell membrane of most renal epithelial cells. Transepithelial sodium transport occurs because apical transport pathways permit Na to move down its electrochemical gradient from tubule lumen to cell, often coupled to the movement of other ions across the same membrane. Most diuretic drugs act by inhibiting apical Na transport pathways. Because apical Na transport pathways are nephron segment specific, each class of diuretic inhibits Na transport predominantly along a single segment of the nephron. As an example, loop diuretics inhibit Na/K/2C1 cotransport at the apical membrane of medullary and cortical thick ascending limb cells. Although loop diuretics have effects along other segments of the nephron (the proximal tubule and perhaps medullary collecting duct), these are relatively minor compared with their effect of inhibiting NaCl reabsorption along the loop of Henle. The axial organization of renal tubules and the nephron segment-specific inhibition of salt transport by diuretics means that diuretics have both direct effects and indirect effects on solute transport along the nephron.

When NaCl reabsorption along the thick ascending limb is inhibited by loop diuretics, the NaCl concentration in fluid that enters the distal tubule is greatly increased (see Fig. 2a). In one study, the Na concentration in fluid entering the distal tubule of rats rose from 42 to 140 mM during acute loop diuretic infusion [15]. The increased luminal NaCl concentration led to increased Na absorption along the distal tubule (from 148 to 361 pmol/min) [15] because NaCl transport varies directly with the luminal NaCl concentration and loop diuretics have little or no effect on ion transport along the distal tubule (see Fig. 2b). The bulk of the increased NaCl transport along the distal tubule appears to result from enhanced transcellular transport via the thiazide-sensitive Na/Cl

Normal

■ Furosemide

Acute Furosemide

Chronic Furosemide

FIGURE 2. Effects of furosemide on ion transport along the thick ascending limb (TAL) and distal tubule (DT). Dots represent NaCl. Under normal conditions (left), the TAL dilutes tubule fluid and the NaCl concentration in fluid entering the DT is low. When furosemide (or other loop diuretic) is administered acutely (middle), NaCl reabsorption along the TAL declines and NaCl concentration in fluid entering the DT rises. When this process continues (right), cells in the DT enlarge and reabsorb more NaCl. Because more NaCl is now reabsorbed by the DT, the amount of NaCl leaving the DT declines back toward control values (compare the amounts leaving the DT in the left and the right panels). (From Ellison, D. H. in Diuretics IV. Exerpta Medica, Amsterdam 1993, with permission).

cotransporter. In microperfused rat distal tubules, raising the luminal NaCl concentration twofold increased transepithelial Na transport by a factor of 3; this increase could be blocked entirely by luminal chlorothiazide [9], The dependence of transepithelial NaCl transport on luminal NaCl concentration probably results from a dependence of the thiazide-sensitive Na/Cl cotransporter on extracellular Na and Cl concentrations [11].

This first level of adaptation to diuretic drugs, exemplified in Fig. 2b, occurs during the period of diuretic-induced natriuresis [43]. The net effect of acute diuretic administration on urinary Na and Cl excretion, therefore, reflects the sum of effects in the diuretic-sensitive segment (inhibition of NaCl reabsorption) and in diuretic-insensitive segments (secondary stimulation of NaCl reabsorption). Although the most clinically important example of this form of adaptation involves loop diuretics, these compensatory processes occur during administration of most classes of diuretics. The importance of compensatory processes to blunt the acute effects of diuretics is exemplified by carbonic an-hydrase inhibitors which inhibit Na transport across cells of the proximal tubule. The proximal tubule reabsorbs approximately 2/3 of the filtered Na load, suggesting that proximal diuretics might be very potent. Instead, because a large portion of the Na that is rejected by the proximal tubule during carbonic anhydrase inhibitor administration is reabsorbed along the loop of Henle and distal tubule, only a fraction escapes into the urine. Carbonic anhydrase inhibitors, therefore, are drugs of only modest potency. As is discussed in Chapter X on Intensive Diuretic Treatment, blockade of immediate adaptive processes enhances the effects of the administered diuretic.

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