Clarification of the site of action of chlorothiazide in the rat nephron.

The saluretic effect of the thiazide diuretics has been attributed to inhibition of sodium reabsorption in the distal nephron of the kidney. Recent micropuncture studies have shown, however, that chlorothiazide administration can also inhibit sodium reabsorption in the proximal convolution. To clarify the site of the saluretic effect of chlorothiazide, these micropuncture studies examined the effect of chlorothiazide on chloride transport in the nephron. The effect of chlorothiazide on chloride transport was studied because chlorothiazide's effectiveness as a saluretic is largely due to its ability to enhance sodium chloride excretion; if only changes in sodium transport are examined, it would be then difficult to determine if sodium as bicarbonate or as chloride is affected, since chlorothiazide can inhibit carbonic anhydrase. One group of rats was studied before and after 15 mg/kg per h chlorothiazide. For comparison, another group of rats was studied before and after 2 mg/kg per h benzolamide, a carbonic anhydrase inhibitor. Fractional chloride delivery from the proximal tubule was similarly increased in both groups from 59.4 to 71.0% by chlorothiazide administration, Pless than 0.0001, and from 54.3 to 68.2% by benzolamide administration, P less than 0.001. The increased delivery very of chloride from the proximal tubule was largely reabsorbed before the early distal tubule as fractional chloride delivery to this site increased only from 5.08 to 7.40% after chlorothiazide administration, P less than 0.001, and from 4.50 to 6.29% after benzolamide administration, P less than 0.01. Benzolamide had no effect on chloride reabsorption in the distal convoluted tubule. However, chlorothiazide administration resulted in a marked decrease in distal tubular chloride reabsorption, the fraction of filtered chloride present at the late distal tubule incresing from 1.24 to 6.25%, P less than 0.001. Fractional chloride excretion in the urine increased from 0.29 to 3.44%, P less than 0.001, after chlorothiazide, but did not change after benzolamide. The influence of chlorothiazide on proximal chloride transport presumably is related to its ability to inhibit renal carbonic anhydrase. However, it is not the effect of chlorothiazide in the proximal convolution but rather its effect in the distal convoluted tubule which is primarily responsible for its ability to be an effective saliuretic.

Characteristics of the relationship between the flow rate of tubular fluid and potassium transport in the distal tubule of the rat.

The flow rate of tubular fluid has been suggested as one of several factors which may influence potassium transport in the distal convoluted tubule of the kidney. In the present micropuncture studies, the relationship between the flow rate of distal tubular fluid and potassium transport was examined in four groups of rats. Three groups of rats (I, II, and IV) were fed normal rat chow before study whereas one group (III) was fed chow containing 10% KCl. Group II received 10-20 mug/kg per h of d-aldosterone throughout the study. Distal tubular potassium transport in groups I, II, and III was examined before and after an increase in the flow rate of distal tubular fluid as induced by the infusion of an isotonic saline-bicarbonate solution equivalent to 10% of body weight. In group IV, distal tubular potassium transport was examined before and after enhancement of the flow rate by the infusion of hypertonic (15%) mannitol. In all four groups, distal tubular potassium secretion increased as the flow rate of tubular fluid increased. The nature of the relationship between distal tubular potassium transport and tubular fluid flow rate, however, was influenced by the extent to which the tubular fluid to plasma potassium ratio in the late distal tubule varied as the flow rate increased. As the flow rate was increased this ratio decreased significantly and to a comparable extent in groups I and II. In groups III and IV, on the other hand, this ratio was essentially identical during hydropenia and after the increase in the flow rate of tubular fluid. As a result, the increment in the amount of potassium present at the late distal tubule, which occurred as the flow rate increased, was significantly greater in groups III and IV than in groups I and II. The contrast in the relationship between the flow rate of distal tubular fluid and potassium transport which were observed, probably reflects differences in the net driving force for cell to lumen potassium movement. Seemingly, the net driving force for potassium movement was maintained, as the flow rate of tubular fluid increased, by chronic potassium loading in group III and by hypertonic mannitol infusion in group IV. In groups I and II, the net driving force for potassium movement decreased as the flow rate of tubular fluid increased. However, the net driving force did not decrease in proportion to the increase in flow rate since potassium secretion was increased by increments in flow rate in these groups as well. We conclude that our results are consistent with the view that the flow rate of tubular fluid is a factor which can affect distal tubular potassium transport. However, the nature of the relationship between the flow rate of tubular fluid and potassium transport appears to depend upon the degree to which the driving force for cell to lumen potassium movement changes as the flow rate is varied.