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).

ZENECA ZM181,037 is a novel eukalemic diuretic from a series of 1,1-diarylcarbin-1-01-2 amines. In contrast to the standard diuretic hydrochlorothiazide, the blood pressure-lowering effect was not observed with ZENECA ZM 181,037 in spontaneously hypertensive rats. ZENECA ZM 181,037 demonstrated a K⁺ channel-blocker profile. In the isolated rat aorta stimulated with 20 mmol/l KC1, both the d- and l-enantiomer of ZENECA ZM 181,037 antagonized the relaxation of cromakalim with mean pK_B values of 6.4 and 6.7, respectively. In the isolated guinea-pig portal vein and urinary detrusor muscle, both enantiomers enhanced the spontaneous myogenic activity at concentrations of 1 µmol/l and higher, in addition to antagonizing the effect of cromakalim. ZENECA ZM 181,037, similar to glibenclamide, prevented a significant increase in ⁸⁶Rb⁺ by cromakalim in both portal vein and detrusor muscle strips; however, ZENECA ZM 181,037, dissimilar to glibenclamide and tolbutamide, did not increase plasma glucose when given orally to dogs. Thus, ZENECA ZM 181,037 is a blocker of the ATP-sensitive K⁺ channel (K_ATP) in vascular and nonvascular tissues. In view of the profound saluresis produced by ZENECA ZM 181,037, the lack of antihypertensive effect appears to result from its blocking activity on K_Aχp in vascular tissues.

ICI 206,970 is a novel eukalemic diuretic from the amino-methylphenol pyrazine series which exhibited a calcium antagonist profile. The isolated rat aorta evaluation and dihydropyridine ligand [³H]-PN 200-110 binding studies demonstrated that ICI 206,970, like verapamil and nifedipine, inhibits vascular smooth muscle tone by inhibiting voltage-sensitive calcium channels. ICI 206,970 produced dose-related hypotensive, negative chronotropic, dromotropic, and coronary vasodilator responses after i.v. injection in anesthetized dogs. ICI 206,970, similar to calcium channel blockers and dissimilar to diuretics, produced an acute antihypertensive effect in spontaneously hypertensive rats (SHR), and significant protection against the development of myocardial hypertrophy in SHR after chronic oral treatment for 28 consecutive days. It is concluded that ICI 206,970 is a calcium channel blocker in addition to its novel eukalemic diuretic property.

No abstract