Mode of action of P2Y12 antagonists as inhibitors of platelet function
Mode of action of P2Y12 antagonists as inhibitors of platelet function
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DOI：
10.1160/th10-07-0482
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发表时间：
2011-01-01
影响因子：
6.7
通讯作者：
Heptinstall, Stan
中科院分区：
文献类型：
--
作者：
Iyu, David;Glenn, Jackie R.;Heptinstall, Stan
P2Y（12）受体拮抗剂是通过阻断二磷酸腺苷（ADP）对P2Y（12）受体的作用来抑制血小板功能的抗血栓药物。然而，一些P2Y（12）受体拮抗剂可能通过其他机制影响血小板功能。本研究的目的是探讨P2Y（12）拮抗剂通过与P2Y（12）受体以外的g蛋白偶联受体相互作用抑制血小板功能的可能性。我们比较了康格瑞洛、替格瑞洛和普拉格雷活性代谢物对血小板聚集和血管扩张剂刺激磷酸化蛋白（VASP）的影响。我们比较了它们与选择性IP、EP4和A（2A）激动剂的作用，它们作用于G(s)偶联受体。这三种P2Y（12）拮抗剂都是adp诱导的血小板聚集的强抑制剂，但只能部分抑制凝血酶受体激活肽（TRAP）或血栓素A(2)模拟物U46619诱导的血小板聚集。此外，在使用apyrase和腺苷脱氨酶去除ADP及其代谢物后，P2Y（12）拮抗剂仅对TRAP或u46619诱导的聚集产生轻微的额外抑制。相反，无论ADP是否被去除，G(s)偶联受体激动剂总是对I聚集产生强烈的抑制作用。其他使用选择性受体激动剂和拮抗剂的实验没有发现任何P2Y（12）拮抗剂通过PAR1、TP、IP、EP4、A（2A）或EP3受体起作用的证据。这三种P2Y（12）拮抗剂均能在同等程度上增强vasp -磷酸化，但其作用远小于IP、EP4和a （2A）激动剂。康格瑞洛、替格瑞洛和普拉格雷对血小板功能的影响主要通过P2Y（12）受体介导，而不是通过另一种g蛋白偶联受体介导。
P2Y(12) receptor antagonists are antithrombotic agents that inhibit platelet function by blocking the effects of adenosine diphosphate (ADP) at P2Y(12) receptors. However, some P2Y(12) receptor antagonists may affect platelet function through additional mechanisms. It was the objective of this study to investigate the possibility that P2Y(12) antagonists inhibit platelet function through interaction with G-protein-coupled receptors other than P2Y(12) receptors. We compared the effects of cangrelor, ticagrelor and the prasugrel active metabolite on platelet aggregation and on phosphorylation of vasodilator-stimulated phosphoprotein (VASP). We compared their effects with those of selective IP, EP4 and A(2A), agonists, which act at G(s)-coupled receptors. All three P2Y(12) antagonists were strong inhibitors of ADP-induced platelet aggregation but only partial inhibitors of aggregation induced by thrombin receptor activating peptide (TRAP) or the thromboxane A(2) mimetic U46619. Further, after removing ADP and its metabolites using apyrase and adenosine deaminase, the P2Y(12) antagonists produced only minor additional inhibition of TRAP or U46619-induced aggregation. Conversely, the G(s)-coupled receptor agonists always produced strong inhibition of I aggregation irrespective of whether ADP was removed. Other experiments using selective receptor agonists and antagonists provided no evidence of any of the P2Y(12) antagonists acting through PAR1, TP, IP, EP4, A(2A) or EP3 receptors. All three P2Y(12) antagonists enhanced VASP-phosphorylation to a small and equal extent but the effects were much smaller than those of the IP, EP4 and A(2A) agonists. The effects of cangrelor, ticagrelor and prasugrel on platelet function are mediated mainly through P2Y(12) receptors and not through another G-protein-coupled receptor.