title: In vitro pharmacological properties of KRH-594, a novel angiotensin II type 1 receptor antagonist.
abstract: 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-cyclopentenec arboxylate, 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 microM) 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.
authors.affiliation: Institute for Medical Research, Wakunaga Pharmaceutical Co., Ltd., Hiroshima, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tamura
authors.forename: M
authors.initials: M
authors.lastname: Okuhira
authors.forename: I
authors.initials: I
authors.lastname: Mikoshiba
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
mesh_terms: D000803:Angiotensin I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011817:Rabbits; D013777:Tetrazoles / Q000494:pharmacology*; D013830:Thiadiazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; C108799:KRH 594; D013777:Tetrazoles; D013830:Thiadiazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000803:Angiotensin I; D019808:Losartan