IN-VITRO PHARMACOLOGICAL PROPERTIES OF KRH-594, A NOVEL ANGIOTENSIN-II TYPE-1 RECEPTOR ANTAGONIST

This report describes the in vitro pharmacological properties of dipot assium 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl] -ylidene]ami nocarbonyl]-1-cyclopentenecarboxylate, called KRH-594, a novel angiote nsin II (AII) type 1 (AT(1)) receptor antagonist. We exposed rabbit ao rtic rings to KRH-594 (0.1 nM) for increasing contact times and observ ed an increasing degree of insurmountable suppression of All-induced c ontractions, KRH-594 (0.01, 0.1 and 1.0 nM) caused a concentration-rel ated, insurmountable suppression of the AII concentration-response cur ve. Repeated washing of rabbit aortic rings preincubated,vith KRH-593 (0.1, 1.0 and 10 nM) slowly reversed the insurmountable suppression, T he marked suppression of AII-induced contractions by KRH-594 (0.1 nM) was restored by co-incubation with losartan (100 nM). KRH-593 (10 mu M ) had no effect on bradykinin-, acetylcholine-, or histamine-induced c ontractions of guinea pig ileum, demonstrating its high specificity fo r AT(1) receptors. These results demonstrate that KRH-594 is a potent, specific and insurmountable AT(1) receptor antagonist, KRH-594 activi ty in rabbit aorta appears to be that of a slowly reversible (pseudo-i rreversible) antagonist.