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首页> 外文期刊>Canadian Journal of Physiology and Pharmacology >Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries.
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Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries.

机译：达鲁森坦是内皮素信号传导和在大动脉和小动脉中均起作用的有效抑制剂。

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Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction. We describe the primary pharmacology of darusentan, a propanoic acid based ERA currently in phase 3 clinical trials for resistant hypertension. Darusentan was tested in membrane-, cell-, and tissue-based assays to determine its biochemical and functional potency. Rat aortic vascular smooth muscle cells (RAVSMs) were characterized using flow cytometry. RAVSM membrane fractions tested in saturation experiments exhibited moderate endothelin receptor density. Receptor counting revealed that >95% of the endothelin receptors in these fractions were the ETA subtype. (S)-Darusentan competed for radiolabeled endothelin binding in RAVSM membranes with single-site kinetics, exhibiting a Ki = 13 nmol/L. (R)-Darusentan exhibited no binding activity. In cultured RAVSMs, endothelin induced increases in inositol phosphate and Ca2+ signaling, both of which were attenuated by (S)-darusentan in a concentration-dependent manner. In isolated endothelium-denuded rat aortic rings, (S)-darusentan inhibited endothelin-induced vascular contractility with a pA2 = 8.1 +/- 0.14 (n = 4 animals; mean +/- SD). (R)-Darusentan had no effect. The vasorelaxant potency of (S)-darusentan did not change when determined in isolated denuded rat mesenteric arterioles, suggesting a similar mode of action in both conductance and resistance arteries. In vascular smooth muscle, (S)-darusentan is an ERA with high affinity for the ET receptor, which in this preparation is predominantly ETA receptors. (S)-Darusentan inhibits endothelin-induced signaling related to pro-contractile activity and is a potent inhibitor of vasoconstriction in large and small arteries.
机译：内皮素是一种有效的血管收缩剂，通常在高血压中被上调。内皮素血管收缩是通过血管平滑肌上存在的G蛋白偶联内皮素A（ETA）受体介导的。内皮素受体拮抗剂（ERAs）已显示出拮抗ET诱导的血管收缩。我们描述了darusentan的主要药理学，darusentan是一种基于丙酸的ERA，目前正在用于耐药性高血压的3期临床试验中。 Darusentan在基于膜，细胞和组织的分析中进行了测试，以确定其生化和功能效价。使用流式细胞仪表征大鼠主动脉血管平滑肌细胞（RAVSM）。在饱和实验中测试的RAVSM膜级分显示出适度的内皮素受体密度。受体计数显示，这些馏分中> 95％的内皮素受体是ETA亚型。 （S）-达鲁森坦以单点动力学竞争RAVSM膜中放射性标记的内皮素结合，表现出Ki = 13 nmol / L。 （R）-达鲁森坦没有表现出结合活性。在培养的RAVSMs中，内皮素诱导的肌醇磷酸和Ca2 +信号传导增加，两者均以浓度依赖性方式被（S）-darusentan减弱。在分离的内皮剥落的大鼠主动脉环中，（S）-darusentan抑制了内皮素诱导的血管收缩，pA2 = 8.1 +/- 0.14（n = 4只动物;平均值+/- SD）。 （R）-达鲁森坦没有作用。在分离的裸露大鼠肠系膜小动脉中测定时，（S）-darusentan的血管舒张能力没有改变，表明在电导和阻力动脉中的作用方式相似。在血管平滑肌中，（S）-darusentan是对ET受体具有高亲和力的ERA，在此制剂中，ET受体主要是ETA受体。 （S）-达鲁森坦抑制内皮素诱导的与收缩活动有关的信号，并且是大动脉和小动脉中血管收缩的有效抑制剂。

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