敌手
药理学
受体
体内
血管收缩
化学
内皮素
内分泌学
内科学
对抗
受体拮抗剂
花生四烯酸
内皮素受体
生物
医学
生物化学
生物技术
酶
作者
Terry J. Opgenorth,Andrew Adler,Samuel V. Calzadilla,William J. Chiou,Brian D. Dayton,Douglas B. Dixon,Laura Gehrke,Lisa E. Hernandez,Scott R. Magnuson,Kennan C. Marsh,Eugene I. Novosad,Thomas W von Geldern,Jerry L. Wessale,Martin Winn,Jinshyun R. Wu-Wong
出处
期刊:PubMed
日期:1996-02-01
卷期号:276 (2): 473-81
被引量:46
摘要
Endothelins (ET) are potent vasoactive peptides implicated in the pathogenesis of a number of vascular diseases. The effects of ET on mammalian organs and cells are initiated by binding to ETA or ETB receptors. In this report, we document the pharmacology of A-127722, a novel ETA-selective receptor antagonist. A-127722 inhibits [125I]ET-1 binding to cloned human ETA and ETB receptors competitively with Ki values of 69 pM and 139 nM, respectively. A-127722 exhibits a dose-dependent inhibition of ET-1-induced arachidonic acid release in human pericardium smooth muscle cells with a pA2 value of 10.5 and inhibits ET-1-induced vasoconstriction in isolated rat aorta with a pA2 value of 9.2. In vivo, A-127722 dose-dependently blocks the pressor response to ET-1 (0.3 nmol/kg i.v.) in conscious rats. Statistically significant (P < .05) antagonism is seen at doses greater than 0.1 mg/kg p.o. Maximal inhibition, at 10 mg/kg, remains constant for at least 8 hr after dosing. No effect is seen on the ETB-mediated transient vasodepressor effect of exogenous ET-1. In conclusion, A-127722 is ETA-selective, orally bioavailable and efficacious for inhibiting the effects of ET in the rat, and A-127722 is the most potent ET receptor antagonist yet reported.
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