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ABSTRACT-ICI 181,037, the most active compound from a series of 1,1-diaryl carbin-1-ol-2 amines, was evaluated for diuretic and cardiovascular activity. In saline loaded rats, the magnitude of water diuresis and saluresis produced by ICI 181,037 (10 mg/kg, p.o.) was equal to that of hydrochlorothiazide. Water diuresis and saluresis produced by ICI 181,037 were enhanced with SKF 525A, ampicillin or neomycin plus lincomycin, suggesting that ICI 181,037 is an active diuretic. In conscious dogs, the saluretic activity of ICI d-181,037 (5 mg/kg, p.o.) was about 80% of the corresponding hydrochlorothiazide value, whereas the 1-isomer demonstrated only minimum saluretic activity. In both rats and dogs, the concurrent kaliuresis after ICI 181,037 or its enan tiomers was minimal as compared to hydrochlorothiazide. Following chronic dosing with diuretic doses, the basal levels of plasma potassium in dogs were not altered. In amphibian in vitro models for mimicking mammalian nephron, ICI 181,037 and its enantiomers demonstrated antinatriferic and antichloriferic activities, suggesting multi ple renal sites of action for this agent. Racemic ICI 181,037 and its isomers reversed ouabain-induced arrhythmia in dogs and/or reduced the ouabain-induced mortality in mice after intravenous administration. It is concluded that ICI 181,037, particularly its d-isomer, is a novel eukalemic diuretic and possesses antiarrhythmic activity.Diuretics have been used as a major treat ment of renal and cardiovascular disorders for more than three decades. The relative success of diuretic therapies has been based upon their relatively low cost, easy titration, good patient tolerability, and few subjective and im mediate side effects. Electrolyte alterations and metabolic abnormalities are the primary adverse effects. There is an abundance of literature suggesting that diuretic-induced hypokalemia may lead to the occurrence of cardiac arrhythmia (1 7), although current opinions on this issue are not necessarily unanimous. Nevertheless, the available data concerning the arrhythmogenic potential of kaliuretic diuretics are substantial enough to warrant some precautions on the part of the clinician (8). It is evident that hypokalemia in duced by diuretics is a cause for concern in clinical practice. Thus, a saluretic agent which induces less urinary potassium loss resulting in eukalemia will be an attractive therapeutic agent. We report here on the pharmacology of ICI 181,037 (R * S * -2-[2-dimethylamino-l-hy droxy-1-(2-methoxy-5 (1, 1-dimethylethyl)-phen yl)propyl) phenoxy]acetamide), a eukalemic diuretic which possesses an antiarrhythmic property (Fig. 1).

We investigated the natriuretic and kaliuretic effect of distal tubular diuretics in saline-loaded spontaneously hypertensive Wistar rats (SHR) from three different sources and normotensive Wistar rats (NWR). Orally administered early distal tubular diuretics (hydrochlorothiazide, chlorthalidone, metolazone, indapamide and cicletanine) caused much less potassium excretion in SHR than in NWR, whereas the magnitude of concurrent natriuresis was similar in both NWR and SHR. The intriguing renal handling of potassium excretion was exemplified by hydrochlorothiazide, for which enhanced kaliuresis was dose dependent in NWR but not in SHR. The doses tested ranged from 1 to 100 mg/kg, p.o. Amiloride, a late distal tubular diuretic, was also evaluated for its effect on sodium and potassium excretion in NWR and SHR. Amiloride produced potassium retention more effectively in NWR than in SHR, although the magnitude of natriuresis was similar. The difference between SHR and NWR with regard to potassium-retaining activity of amiloride was consistent at all doses tested (1-30 mg/kg, p.o.). In conclusion, it was suggested that SHR appear to have a genetic defect in potassium transport in the distal nephron.

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