Synergistic Inhibition of Both P2Y1 and P2Y12 Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis.
Synergistic Inhibition of Both P2Y1 and P2Y12 Adenosine Diphosphate Receptors As Novel Approach to Rapidly Attenuate Platelet-Mediated Thrombosis.
复制标题
对P2Y1和P2Y12腺苷受体的协同抑制作用是快速减弱血小板介导的血栓形成的新方法。
DOI：
10.1161/atvbaha.115.306885
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发表时间：
2016-03
期刊：
影响因子：
--
通讯作者：
Przyklenk K
中科院分区：
文献类型：
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作者：
Gremmel T;Yanachkov IB;Yanachkova MI;Wright GE;Wider J;Undyala VV;Michelson AD;Frelinger AL 3rd;Przyklenk K
与目前已批准的二磷酸腺苷(ADP)受体拮抗剂不同，新的二腺苷四磷酸衍生物GLS-409不仅针对P2Y12，还针对第二个人血小板ADP受体P2Y1，因此可能成为一种有前途的抗血小板药物候选药物。本研究首次对GLS-409的体内抗血栓作用进行了研究。我们研究了(1)GLS-409对麻醉大鼠激动剂诱导的血小板聚集的体内作用，(2)GLS-409的抗血栓活性及其对犬血小板介导的冠状动脉血栓形成模型出血时间的影响，以及(3)GLS-409对激动剂诱导的血小板聚集的抑制作用以及对服用阿司匹林前和后2小时的选择性P2Y1和P2Y12抑制作用的比较。体内应用GLS-409可显著抑制ADP和胶原刺激的大鼠血小板聚集。此外，在我们的不稳定型心绞痛犬模型中，GLS-409可减弱循环血流变化，即血小板介导的体内血栓形成。冠状动脉通畅性的改善伴随着出血时间无显著增加30%。值得注意的是，GLS-409在不影响大鼠和狗的血流动力学的情况下发挥其作用。最后，GLS-409的体外治疗显示出与康瑞尔和选择性P2Y1抑制剂MRS 2179合用对阿司匹林服药前和服药后2小时内人富含血小板血浆和全血中激动剂刺激的血小板聚集的影响。GLS-409对P2Y1和P2Y12 ADP受体的协同抑制作用可立即减弱血小板介导的血栓形成，并有效地阻断激动剂刺激的血小板聚集，而与阿司匹林同时治疗无关。
Unlike currently approved adenosine diphosphate (ADP) receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y12 but also the second human platelet ADP receptor P2Y1, 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. 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 P2Y1 and P2Y12 inhibition in vitro in samples from healthy human subjects before and 2 hours after aspirin intake. In vivo treatment with GLS-409 significantly inhibited ADP- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic flow variation, i.e., platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a non-significant 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 P2Y1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 hours after aspirin intake. Synergistic inhibition of both P2Y1 and P2Y12 ADP receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.