Tubular chloride transport and the mode of action of some diuretics

Diuretic drugs have been the subject of intensive investigation and speculation, owing to their importance in therapy. Since it was known that the diuretics act to inhibit the reabsorption of sodium chloride by the renal tubules, studies were aimed at elucidating the mechanism of transport of salt in the kidney and how the drugs affect it. Generally the emphasis was on active sodium transport, which was believed to be the primary process. Ussing and Ze-rahn [1] had shown that absorption of salt through frog skin is driven by active transport of sodium. The sodium transport causes a voltage which is negative outside the frog. Chloride transport is passive, driven by the voltage. In the segments of the nephron that were first studied directly by micropuncture, the mechanism of salt transport was apparently similar to that in frog skin. The most important finding was that the voltage across both proximal and distal tubules was negative in the lumen (corresponding to the outside of the frog). Later, some suggested that there might also be active chloride transport in proximal [2] and distal [3] tubules, but the conclusion was controversial and even its advocates believed that the active chloride transport, if any, was ancillary to active sodium transport. With certain notable exceptions [4, 5], investigators also believed that diuretic drugs cause natruiresis by inhibiting the active sodium transport across renal tubules. In order to analyze the actions of the drugs, their effects were tested on various nonrenal tissues such as frog skin and toad bladder that actively transport sodium and are more easily studied than are kidney tubules. The results were disappointing. The sodium-transporting tissues are not very sensitive to diuretic drugs, and, although high concentrations of the drugs have effects, these are difficult to relate back to the kidney. There was considerable progress in developing better diuretics, but this was empirical, based on the synthesis and testing of chemical analogues of known diuretics, and was not guided to an important extent by principles deduced from investigation of the mechanism of drug action. In addition, the studies of the action of diuretic drugs which emphasized sodium transport failed to address an important problem. Sodium transport is ubiquitous in the body, and, if it were inhibited to even a minor degree in such tissues as nerve, the result could be alarming. Therefore, how do diuretics inhibit sodium transport so extensively in the kidney and yet have so little effect elsewhere in the body? As evidenced elsewhere in this symposium, contemporary studies continue to support the traditional belief that active sodium transport is the basic process in proximal tubules, distal convoluted tubules and the collecting ducts. However, the findings in the thick ascending limb of Henle's loop or, as we prefer to call it, the "diluting segment" 1 are in striking disagreement with the traditional concept. In this segment it is now apparent that active chloride transport, rather than sodium transport, is the primary event, and that the major effect of several important diuretics is to inhibit the active chloride transport, rather than sodium transport, as previously believed. In what follows, I will first review the evidence that there is active chloride transport in the diluting segment, then discuss the effects of some diuretic drugs on this chloride transport.