Cardiovascular Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
Platelets. 2011;22(7):504-15. doi: 10.3109/09537104.2011.576284. Epub 2011 May 19.
Several antiplatelet drugs that are used or in development as antithrombotic agents, such as antagonists of P2Y₁₂ and EP3 receptors, act as antagonists at G(i)-coupled receptors, thus preventing a reduction in intracellular cyclic adenosine monophosphate (cAMP) in platelets. Other antiplatelet agents, including vascular prostaglandins, inhibit platelet function by raising intracellular cAMP. Agents that act as antagonists at G(i)-coupled receptors might be expected to promote the inhibitory effects of agents that raise cAMP. Here, we investigate the ability of the P2Y₁₂ antagonists cangrelor, ticagrelor and prasugrel active metabolite (PAM), and the EP3 antagonist DG-041 to promote the inhibitory effects of modulators of platelet aggregation that act via cAMP. Platelet aggregation was measured by platelet counting in whole blood in response to the TXA₂ mimetic U46619, thrombin receptor activating peptide and the combination of these. Vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) was measured using a cytometric bead assay. Cangrelor always increased the potency of inhibitory agents that act by raising cAMP (PGI₂, iloprost, PGD₂, adenosine and forskolin). Ticagrelor and PAM acted similarly to cangrelor. DG-041 increased the potency of PGE₁ and PGE₂ as inhibitors of aggregation, and cangrelor and DG-041 together had more effect than either agent alone. Cangrelor and DG-041 were able to increase the ability of agents to raise cAMP in platelets as measured by increases in VASP-P. Thus, P2Y₁₂ antagonists and the EP3 antagonist DG-041 are able to promote inhibition of platelet aggregation brought about by natural and other agents that raise intracellular cAMP. This action is likely to contribute to the overall clinical effects of such antagonists after administration to man.
几种抗血小板药物，如 P2Y₁₂和 EP3 受体拮抗剂，作为抗血栓药物正在使用或处于开发阶段，它们作为 G(i)偶联受体的拮抗剂，从而防止血小板中环磷酸腺苷（cAMP）的减少。其他抗血小板药物，包括血管前列腺素，通过提高细胞内 cAMP 来抑制血小板功能。作为 G(i)偶联受体拮抗剂的药物可能会促进提高 cAMP 的药物的抑制作用。在这里，我们研究了 P2Y₁₂拮抗剂坎格瑞洛、替格瑞洛和普拉格雷活性代谢物（PAM）以及 EP3 拮抗剂 DG-041 促进通过 cAMP 作用的血小板聚集调节剂的抑制作用的能力。通过全血中的血小板计数测量血小板聚集对 TXA₂模拟物 U46619、凝血酶受体激活肽和这些物质的组合的反应。使用流式细胞术珠测定法测量血管舒张刺激磷酸蛋白磷酸化（VASP-P）。坎格瑞洛总是增加通过提高 cAMP（PGI₂、伊洛前列素、PGD₂、腺苷和福司可林）起作用的抑制剂的效力。替格瑞洛和 PAM 与坎格瑞洛的作用相似。DG-041 增加了 PGE₁和 PGE₂作为聚集抑制剂的效力，坎格瑞洛和 DG-041 一起的效果比单独使用任何一种药物都要好。坎格瑞洛和 DG-041 能够增加药物在血小板中提高 cAMP 的能力，如通过 VASP-P 的增加来测量。因此，P2Y₁₂拮抗剂和 EP3 拮抗剂 DG-041 能够促进由天然和其他提高细胞内 cAMP 的药物引起的血小板聚集的抑制。这种作用可能有助于此类拮抗剂在人类给药后的总体临床效果。
