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Ethacrynic acid (MK-595) 1 is a new orally active saluretic agent structurally unrelated to organomercurial or benzothiadiazine diuretics (2). Its biological properties in experimental animals were first studied by Baer, Russo, Michaelson, and Beyer (3, 4), who reported it to be a natriuretic drug more potent than chlorothiazide and suggested that it might have a novel mode of action. Clinically, its potency seems to be comparable to parenterally administered organomercurials, and it has been effective in patients previously refractory to other diuretics (5, 6). Because of the potential importance of this drug as an effective agent in the treatment of edema, the present study was undertaken to gain knowledge of the site or sites of action of the drug in the human kidney by determining its effects on urinary dilution and concentration. Knowledge of the mechanisms of urinary concentration and dilution, recently reviewed by Gottschalk (7) and Ullrich, Kramer, and Boylan (8), has provided a basis for studying the locus of action of diuretics in the kidney of intact subjects. In the normal kidney, after reabsorption of approximately two-thirds of filtered sodium and water in isotonic proportions in the proximal convoluted tubule, the remaining urine may be

Effects of Ethacrynic Acid (a New Saluretic Agent) on Renal Diluting and Concentrating Mechanisms: Evidence for Site of Action in the Loop of Henle*