K. Tamura et al., IN-VITRO PHARMACOLOGICAL PROPERTIES OF KRH-594, A NOVEL ANGIOTENSIN-II TYPE-1 RECEPTOR ANTAGONIST, Biological & pharmaceutical bulletin, 20(8), 1997, pp. 850-855
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.