1991 Volume 57 Issue 3 Pages 263-277
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 enantiomers 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 multiple 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.
