IN-VIVO PHARMACOLOGY OF L-159,913, A NEW HIGHLY POTENT AND SELECTIVE NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST

The present study was designed to characterize the in vivo pharmacolog y of L-159,913 2-(trifluoromethylphenyl]-3H-1,2,4-triazol-3-one}; a po tent All receptor antagonist. In normotensive rats, dogs, rhesus monke ys, and chimpanzees, L-159,913 inhibited All-induced elevations in blo od pressure. In conscious rats, the relative potencies (ED(50)) were 0 .51 mg/kg i.v. and 0.72 mg/kg p.o. Duration of action with single i.v. or p.o, doses exceeded 6 hr in rats. L-159,913 was 3 times less poten t than losartan in rats and equipotent to losartan in monkeys. All ind uced elevation of plasma aldosterone in rats was also inhibited by L-1 59,913. L-159,913 was antihypertensive in high renin hypertensive rats (aortic coarctation). The maximum hypotensive response to an acute do se of L-159,913 (10 mg/kg, po) was equal to that of enalaprilat (0.3 m g/kg, iv) in this renin dependent animal model. In conscious normotens ive dogs, L-159,913 had a moderate diuretic, natriuretic and kaliureti c response with no effect on glomerular filtration rate, effective ren al plasma flow or filtration fraction, suggesting a tubular site of ac tion. L-159,913 is a selective and potent Ail receptor antagonist with good oral activity, long duration of action and antihypertensive effi cacy.