摘要：This report describes the in vitro pharmacological properties of dipotassium (Z)-2-[[5-ethyl-3-[2'(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1, 3, 4-thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarboxylate, called KRH-594, a novel angiotensin II (AII) type 1 (AT1) receptor antagonist. We exposed rabbit aortic rings to KRH-594 (0.1 nM) for increasing contact times and observed an increasing degree of insurmountable suppression of AII-induced contractions. KRH-594 (0.01, 0.1 and 1.0 nM) caused a concentration-related, insurmountable suppression of the AII concentration-response curve. Repeated washing of rabbit aortic rings preincubated with KRH-594 (0.1, 1.0 and 10 nM) slowly reversed the insurmountable suppression. The marked suppression of AII-induced contractions by KRH-594 (0.1 nM) was restored by co-incubation with losartan (100 nM). KRH-594 (10 μM) had no effect on bradykinin-, acetylcholine-, or histamine-induced contractions of guinea pig ileum, demonstrating its high specificity for AT1 receptors. These results demonstrate that KRH-594 is a potent, specific and insurmountable AT1 receptor antagonist. KRH-594 activity in rabbit aorta appears to be that of a slowly reversible (pseudo-irreversible) antagonist.
关键词：KRH-594;angiotensin II receptor;insurmountable antagonism
