The Site of Action of Furosemide and Other Sulfonamide Diuretics in the Dog.

The discovery of the countercurrent multiplier system as the mechanism responsible for the concentration and dilution of the urine has provided a framework for the identification of the site of action of diuretic drugs. Agents that act at a single anatomic site in the nephron can be expected to alter the pattern of urine flow in a predictable way. A drug that acts solely in the proximal convoluted tubule, by causing the delivery of increased amounts of filtrate to the loop of Henle and the distal convolution, would augment the clearance of solute-free water (CH2o) during water diuresis and the reabsorption of solute-free water (TCHO) during water restriction. In contrast, drugs that inhibit sodium reabsorption in Henle's loop would impair both CHSo and TCHO. Finally, drugs that act only in the distal tubule would reduce CHSo but not TcH2o (1). It is possible, however, that a diuretic drug might inhibit sodium reabsorption at multiple sites. Under such circumstances, localization of the areas of the nephron where the drug acts is far more difficult, since the effects of action in one segment might alter or obscure the effects on another. A new sulfonamide diuretic, furosemide, 4-chloro-N-(2-furylmethyl)-5-sulfonylanthranilic acid (2), offers several advantages in the study of localization of action: a) it is extremely potent, and therefore produces large effects; and b) its duration of action is brief, thereby facilitating multiple studies during a single experiment. A study * of furosemide was, therefore, undertaken to ex plore its effects on water excretion during hy-dration and hydropenia, and on potassium excre-tion during potassium loading. In addition, the diuretic effect of furosemide was compared to three other sulfonamide diuretics: chlorothiazide, chlor-thalidone, and benzhydroflumethiazide. The conventional sulfonamide diuretics resulted in the excretion of about 10% of filtered sodium and inhibited CQ2o without decreasing TCH2O. In contrast, as much as 38% of filtered sodium was excreted during furosemide diuresis, and both CH20 and TCHSo were inhibited. None of the diu-retics had an inhibitory effect on potassium secretion. The effects of the conventional sulfonamide diuretics can be explained by a single site of action distal to the loop of Henle. In contrast, furose-mide clearly has a potent effect in the ascending limb of Henle's loop and probably in the proximal convoluted tubule as well. Methods A total of 50 experiments was performed on 40 dogs. All dogs were fasted overnight before each study. Mild pentothal anesthesia was induced …