P2Y12
二磷酸腺苷
坎格雷洛
血小板
药理学
抗血栓
腺苷
体内
P2Y受体
兴奋剂
阿司匹林
嘌呤能受体
血小板活化
出血时间
化学
医学
氯吡格雷
受体
内科学
生物
血小板聚集
生物技术
作者
Thomas Gremmel,Ivan B. Yanachkov,Milka Yanachkova,George E. Wright,Joseph M. Wider,Vishnu Undyala,Alan D. Michelson,Andrew L. Frelinger,Karin Przyklenk
标识
DOI:10.1161/atvbaha.115.306885
摘要
Objective— Unlike currently approved adenosine diphosphate receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y 12 but also the second human platelet adenosine diphosphate receptor P2Y 1 and may, therefore, be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409. Approach and Results— We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y 1 and P2Y 12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited adenosine diphosphate- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, that is, platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a nonsignificant 30% increase in bleeding time. Of note, GLS-409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y 1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. Conclusions— Synergistic inhibition of both P2Y 1 and P2Y 12 adenosine diphosphate receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.
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