Characterization of angiotensin II antagonism displayed by Ib, a novel nonpeptide angiotensin AT₁ receptor antagonist

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• 作者：Jinhui Wu ; Qiujuan Wang ; Jiyuan Guo ; Zheyi Hu ; Zhiyong Yin ; Jinyi Xu ; Xiaoming Wu
• 关键词：Ib ; Angiotensin II ; AT₁ receptor ; Insurmountable antagonism ; Hypertension
• 刊名：European Journal of Pharmacology
• 出版年：2008
• 出版时间：28 July 2008
• 年：2008
• 卷：589
• 期：1-3
• 页码：220-224
• 全文大小：527 K

文摘

The pharmacologic profile of Ib, 5-n-butyl-4-{4-[2-(1H-tetrazole-5-yl)-1H-pyrrol-1-yl]phenylmethyl}-2,4-dihydro-2-(2,6-dichloridephenyl)-3H-1,2,4-triazol-3-one, a novel nonpeptide angiotensin AT₁ receptor antagonist, was investigated by receptor-binding studies, functional in vitro assays with rabbit and rat aorta, and in vivo experiments in rats. Ib inhibited [¹²⁵I] angiotensin II binding to AT₁ receptors in rat liver membranes (K_i = 2.5 ± 0.5 nM) and did not interact with AT₂ receptors in bovine cerebellar membranes. In functional studies with rat and rabbit aorta, Ib inhibited the contractile response to angiotensin II (pD₂′ value: 7.43 and 7.29, respectively) with a significant reduction in the maximum. In pithed rats, Ib inhibited the angiotensin II induced pressor response in a dose-related manner. After intravenous administration, Ib produced a dose-dependent antihypertensive effects in spontaneously hypertensive rats and renal hypertensive rats. These results suggest that Ib is a potent angiotensin AT₁ selective receptor antagonist with a mode of insurmountable antagonism.