ANTIHYPERTENSIVE ACTIVITY OF A NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONIST, YM358, IN RATS AND DOGS

The antihypertensive activity of YM358, 2,7-diethy-5-[[2'-(1 H-tetrazo l-5-yl)biphenyl-4-yl]methyl]-5 H-pyrazolo[1,5-b][1.2,4]triazole potass ium salt monohydrate, a new nonpeptide angiotensin II receptor antagon ist, was characterized in rats and dogs. In conscious rats, YM358 afte r a single oral administration (1-30 mg/kg) lowered blood pressure. Th e rank order of hypotensive potency of YM358 in conscious rats was 2-k idney, 1-clip renal hypertensive rats > spontaneously hypertensive rat s > normotensive rats on the basis of maximum hypotension. YM358 also caused decreases in blood pressure in 2-kidney, 1-clip renal hypertens ive dogs and furosemide-treated dogs. Repeated administration of YM358 to 2-kidney, 1-clip renal hypertensive rats for 28 days produced a st able and long-lasting antihypertensive effect without influencing circ adian blood pressure and heart rate rhythms. No reflex tachycardia was observed in any animals of either species treated with YM358. Therefo re, the pharmacological profile of this compound indicates that YM358 has potential as a useful antihypertensive agent. (C) 1997 Elsevier Sc ience B.V.