Chou T-C, Lin Y-F, Wu W-C, Chu K-M
Department of Physiology, National Defense Medical Center, Taipei, Taiwan.
Br J Pharmacol. 2008 Mar;153(6):1281-7. doi: 10.1038/bjp.2008.19. Epub 2008 Feb 11.
It has been found that 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert various vascular protective effects, beyond their cholesterol-lowering property, including inhibition of platelet-dependent thrombus formation. The objective of the present study was to determine whether the nitric oxide (NO)/cyclic GMP-mediated processes in platelets contribute to the anti-aggregatory activity of simvastatin.
After rabbit platelets were incubated with simvastatin for 5 min, aggregation was induced and the platelet aggregation, nitric oxide synthase activity, guanylyl cyclase activity, NO and cyclic GMP formation were measured appropriately.
Treatment with simvastatin concentration-dependently inhibited platelet aggregation induced by collagen or arachidonic acid with an IC(50) range of 52-158 microM. We also demonstrated that simvastatin (20-80 microM) concentration-dependently further enhanced collagen-induced NO and cyclic GMP formation through increasing NOS activity (from 2.64+/-0.12 to 3.52+/-0.21-5.10+/-0.14 micromol min(-1) mg protein(-1)) and guanylyl cyclase activity (from 142.9+/-7.2 to 163.5+/-17.5-283.8+/-19.5 pmol min(-1) mg protein(-1)) in the platelets. On the contrary, inhibition of platelet aggregation by simvastatin was markedly attenuated (by about 50%) by addition of a nitric oxide synthase inhibitor, a NO scavenger or a NO-sensitive guanylyl cyclase inhibitor. The anti-aggregatory effects of simvastatin were significantly increased by addition of a selective inhibitor of cyclic GMP phosphodiesterase.
Our findings indicate that enhancement of a NO/cyclic GMP-mediated process plays an important role in the anti-aggregatory activity of simvastatin.
已发现3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）除具有降低胆固醇的特性外，还发挥多种血管保护作用，包括抑制血小板依赖性血栓形成。本研究的目的是确定血小板中一氧化氮（NO）/环磷酸鸟苷（cGMP）介导的过程是否有助于辛伐他汀的抗聚集活性。
将兔血小板与辛伐他汀孵育5分钟后，诱导聚集，并适当测量血小板聚集、一氧化氮合酶活性、鸟苷酸环化酶活性、NO和cGMP的生成。
辛伐他汀处理以浓度依赖性方式抑制胶原蛋白或花生四烯酸诱导的血小板聚集，IC50范围为52-158微摩尔。我们还证明，辛伐他汀（20-80微摩尔）通过增加血小板中的一氧化氮合酶活性（从2.64±0.12增加到3.52±0.21-5.10±0.14微摩尔·分钟-1·毫克蛋白-1）和鸟苷酸环化酶活性（从142.9±7.2增加到163.5±17.5-283.8±19.5皮摩尔·分钟-1·毫克蛋白-1），以浓度依赖性方式进一步增强胶原蛋白诱导的NO和cGMP生成。相反，添加一氧化氮合酶抑制剂、NO清除剂或NO敏感性鸟苷酸环化酶抑制剂可使辛伐他汀对血小板聚集的抑制作用明显减弱（约50%）。添加环磷酸鸟苷磷酸二酯酶的选择性抑制剂可显著增强辛伐他汀的抗聚集作用。
我们的研究结果表明，增强NO/cGMP介导的过程在辛伐他汀的抗聚集活性中起重要作用。
