The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood
The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood
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DOI：
10.1111/bph.13286
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发表时间：
2015-11-01
影响因子：
7.3
通讯作者：
Walter, U.
中科院分区：
文献类型：
--
作者：
Reiss, C.;Mindukshev, I.;Walter, U.
背景和目的刺激可溶性鸟苷酸环化酶（sGC）是治疗多种心血管疾病的一种有价值的治疗策略。 sGC 刺激剂利奥西呱已被批准用于治疗两种形式的肺动脉高压。血小板含有大量的sGC，在止血调节中发挥关键作用。因此，我们研究了利奥西呱对血小板功能的影响。实验方法研究了利奥西呱治疗对人血小板活化和聚集的影响。通过比较野生型和血小板特异性 sGC 敲除小鼠来确定利奥西呱的 sGC 特异性作用。 主要结果利奥西呱诱导人血小板中的 cGMP 合成和随后的 PKG 激活，表明抑制作用是由 cGMP 信号传导介导的。当利奥西呱不抑制 sGC 敲除血小板时，这一发现得到了证实。在洗涤的人血小板中，100nM 利奥西呱可减少 ADP 诱导的 GPIIb/IIIa 激活，而需要高 10 倍的浓度才能减少惊厥素刺激的 GPIIb/IIIa 激活。 Riociguat 抑制 ADP 诱导的血小板形状变化和聚集，而 ATP 诱导的形状变化不受影响。然而，在PRP和全血中，需要50-100M利奥西呱来抑制血小板活化和聚集。利奥西呱与伊洛前列素联合显着抑制血小板聚集，甚至在全血中也是如此。 结论和意义利奥西呱仅在浓度高于50M时才抑制全血中的血小板活化，而利奥西呱治疗患者的血浆浓度为150至500nM。这一发现表明利奥西呱治疗不会影响患者的血小板功能。然而，应考虑利奥西呱与伊洛前列素协同作用抑制血小板活化的可能性。
Background and PurposeStimulation of soluble guanylyl cyclase (sGC) is a valuable therapeutic strategy for the treatment of several cardiovascular diseases. The sGC stimulator riociguat has been approved for the treatment of two forms of pulmonary hypertension. Platelets contain large amounts of sGC and play a key role in the regulation of haemostasis. Therefore, we investigated the effects of riociguat on platelet function.Experimental ApproachThe effect of riociguat treatment on human platelet activation and aggregation was investigated. The sGC-specific effects of riociguat were determined by comparing wild-type and platelet-specific sGC-knockout mice.Key ResultsRiociguat induced cGMP synthesis and subsequent PKG activation in human platelets, suggesting that the inhibitory effects are mediated by cGMP signalling. This finding was confirmed when sGC-knockout platelets were not inhibited by riociguat. In washed human platelets, 100nM riociguat reduced ADP-induced GPIIb/IIIa activation, while a 10-fold higher concentration was required to reduce convulxin-stimulated GPIIb/IIIa activation. Riociguat inhibited ADP-induced platelet shape change and aggregation, while ATP-induced shape change remained unaffected. However, in PRP and whole blood, 50-100M riociguat was required to inhibit platelet activation and aggregation. Riociguat in combination with iloprost significantly inhibited platelet aggregation, even in whole blood.Conclusions and ImplicationsRiociguat inhibits platelet activation in whole blood only at concentrations above 50M, while the plasma concentrations in riociguat-treated patients are 150 to 500nM. This finding indicates that riociguat treatment does not affect platelet function in patients. Nevertheless, the possibility that riociguat acts synergistically with iloprost to inhibit platelet activation should be considered.