EFFICACY OF SR-47436 (BMS-186295), A NONPEPTIDE ANGIOTENSIN AT(1) RECEPTOR ANTAGONIST IN HYPERTENSIVE RAT MODELS

The efficacy of SR 47436 (BMS-186295), 2-n-butyl-3-[(2'-(1 l-4-yl)meth yl]-1,3-diaza-spiro[4,4]non-1-en-4-one, a non-peptide angiotensin AT(1 ) receptor antagonist, was characterized in various conscious hyperten sive rat models. In spontaneously hypertensive rats, single intravenou s or oral doses of SR 47436 induced mild to modest antihypertensive ef fects. No tolerance of the antihypertensive effect was observed when t he oral treatment was extended to 15 days. SR 47436 was highly effecti ve to lower blood pressure in high renin-dependent hypertensive models such as two-kidney, one-clip renal hypertensive rats and renal artery -ligated hypertensive rats. In this last model, intravenous or oral ad ministration of the angiotensin II antagonist produced a dose-dependen t decrease in blood pressure. When injected after the maximal effectiv e dose, enalapril did not induce any further decrease in blood pressur e. Furthermore, the antihypertensive effect elicited after a single or al dose (10 mg/kg) was long-lasting (at least 24 h). The simultaneous blunting effect of the angiotensin II-induced blood pressure increase indicated clearly that the antihypertensive effect was due to the bloc kade of vascular angiotensin AT(1) receptors. As expected, the angiote nsin AT(1) receptor antagonist did not show any efficacy in deoxycorti costerone acetate hypertensive rats, with a-angiotensin system. In gen etic and renal hypertensive rats, the antihypertensive effect induced after acute dosing of SR 47436 was similar to that observed after losa rtan and enalapril. A reflex tachycardia accompanied the antihypertens ive effect only after intravenous treatment with either SR 47436 or lo sartan. These results show that this angiotensin II antagonist, SR 474 36, is an effective and long-lasting antihypertensive agent in rats.