National Heart and Lung Institute, Imperial College, London, UK.
Eur J Pharmacol. 2011 Jan 25;651(1-3):152-8. doi: 10.1016/j.ejphar.2010.11.011. Epub 2010 Nov 28.
The role of endogenous nitric oxide in regulating platelet function in vivo is incompletely understood. The enzymic and anatomic sources of bioactive NO remain unclear and the consequences of the differences in endothelial function between males and females to platelet responsiveness are not known. We employed a mouse model of platelet thromboembolism to assess platelet aggregation in vivo along with supporting in vitro studies to investigate these issues. Pharmacological nitric oxide synthase (NOS) inhibition protracted the duration of thromboembolic responses to ADP (adenosine diphosphate) and enhanced in vivo platelet aggregation following activation of the coagulation cascade. Collagen induced in vivo platelet aggregation was enhanced in female eNOS(-/-) mice and the NOS inhibitor L-NAME (Nω-Nitro-l-arginine methyl ester hydrochloride) potentiated collagen induced thromboembolism although selective iNOS and nNOS antagonists had no effect. None of the NOS inhibitors tested had significant effects on platelet aggregation in isolated whole blood. In conclusion, endogenous NO derived from eNOS in the vascular endothelium is a critical regulator of platelet function in vivo in both males and females with negligible roles of iNOS and nNOS. Despite the expression of NOS enzymes in circulating blood elements, there is no evidence of a functional role of endogenous NO from these cells in regulating platelets. eNOS and its up- and down-stream mediators are therefore potential anti-thrombotic targets.
内源性一氧化氮在调节体内血小板功能中的作用尚不完全清楚。生物活性一氧化氮的酶和解剖学来源仍不清楚，男性和女性之间内皮功能的差异对血小板反应性的影响也不清楚。我们采用血小板血栓栓塞的小鼠模型来评估体内血小板聚集，并进行了支持性的体外研究来探讨这些问题。药理学一氧化氮合酶（NOS）抑制剂延长了 ADP（腺苷二磷酸）诱导的血栓栓塞反应的持续时间，并增强了凝血级联激活后的体内血小板聚集。与野生型小鼠相比，雌性 eNOS(-/-) 小鼠体内胶原诱导的血小板聚集增强，NOS 抑制剂 L-NAME（Nω-硝基-L-精氨酸甲酯盐酸盐）增强了胶原诱导的血栓栓塞，尽管选择性 iNOS 和 nNOS 拮抗剂没有影响。在分离的全血中，测试的任何一种 NOS 抑制剂均对血小板聚集没有显著影响。总之，血管内皮细胞中的 eNOS 产生的内源性 NO 是调节体内血小板功能的关键调节剂，iNOS 和 nNOS 的作用可以忽略不计。尽管循环血液成分中表达了 NOS 酶，但没有证据表明这些细胞产生的内源性 NO 在调节血小板方面具有功能作用。因此，eNOS 及其上下游介质是潜在的抗血栓靶点。
