Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation
Shear-dependent suppression of platelet thrombus formation by phosphodiesterase 3 inhibition requires low levels of concomitant Gs-coupled receptor stimulation
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DOI：
10.1160/th10-07-0439
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发表时间：
2011-03-01
影响因子：
6.7
通讯作者：
Handa, Makoto
中科院分区：
文献类型：
--
作者：
Yoslhida, Hideo;Okamura, Yosuke;Handa, Makoto
磷酸二酯酶（PDE）3抑制剂通过维持细胞内环磷酸腺苷水平升高发挥有效的抗血小板作用，但不延长出血时间。为了解决这一差异，我们假设PDE3抑制剂有效抑制由血小板受体GPIb/V/IX与其配体血管性血友病因子（VWF）相互作用引发的剪切诱导血小板血栓形成，因为与止血栓形成相比，动脉血栓形成更依赖于剪切应力。为了验证这一假设，我们比较了K-134（一种PDE3抑制剂）、替罗非班（一种GPIIb/IIIa抑制剂）和乙酰水杨酸（ASA）在体外流动条件下对利司他汀诱导的VWF或胶原表面血小板聚集和血小板血栓形成的影响。K-134抑制GPIIb/ iiia依赖性血小板聚集的程度与替罗非班相同，比ASA更有效。同样，K-134和梯罗非班在高剪切作用下，有效抑制VWF或胶原表面稳定的血小板血栓形成（血小板牢固粘附并随后聚集），而ASA仅抑制聚集。值得注意的是，只有在低浓度PGE1存在时，K-134的抑制作用才变得明显。这些抑制剂不能阻断剪切诱导的血小板通过GPIb/V/IX与VWF的初始接触。相反，在低剪切作用下，K-134对胶原表面血小板聚集的抑制作用低于替罗非班或ASA。在低水平腺苷酸环化酶刺激剂存在的情况下，观察到PDE3抑制剂对血小板血栓形成的剪切依赖性抑制可能有助于高治疗效益和低出血风险。
Phosphodiesterase (PDE)3 inhibitors exert potent antiplatelet effects through maintaining elevated intracellular cyclic adenosine monophosphate levels, but do not prolong bleeding time. To resolve this discrepancy, we hypothesised that PDE3 inhibitors effectively suppress shear-induced platelet thrombus formation initiated by the interaction of the platelet receptor GPIb/V/IX with its ligand, von Willebrand factor (VWF), since arterial thrombosis is more dependent on shear stress as compared with haemostatic plug formation. To test the hypothesis, we compared the in vitro effects of K-134 (a PDE3 inhibitor), tirofiban (a GPIIb/IIIa inhibitor) and acetylsalicylic acid (ASA) on ristocetin-induced platelet aggregation and platelet thrombus formation on VWF or collagen surfaces under flow conditions. K-134 inhibited GPIIb/IIIa-dependent platelet aggregation to the same extent as tirofiban and more potently than ASA. Likewise, K-134 and tirofiban effectively inhibited stable platelet thrombus formation (platelet firm adhesion and subsequent aggregation) on the VWF or collagen surface under high shear, but ASA only inhibited aggregation. Notably, inhibition by K-134 became evident only when a low concentration of PGE1 was present. These inhibitors did not block shear-induced initial platelet contact with VWF via GPIb/V/IX. In contrast, under low shear, the inhibitory effects of K-134 on platelet aggregation on the collagen surface were lower than tirofiban or ASA. The observed shear-dependent suppression of platelet thrombus formation by PDE3 inhibitor in the presence of low levels of adenylate cyclase stimulator may contribute to high therapeutic benefit with low risk of bleeding.