Matsuno H, Kozawa O, Ueshima S, Matsuo O, Collen D, Uematsu T
Department of Pharmacology, Gifu University School of Medicine, Tsukasa-machi 40, Gifu 500, Japan.
Br J Pharmacol. 2000 Oct;131(4):858-64. doi: 10.1038/sj.bjp.0703639.
The interaction of fibrinolytic components with GPIb/V/IX of platelets on thrombus formation, was investigated in mice deficient in tissue type (tPA-/-), urokinase type plasminogen activator (uPA-/-) or plasminogen activator inhibitor-1 (PAI-1-/-) and in their wild type control (tPA+/+, uPA+/+, PAI-1+/+). A thrombus was induced in the murine carotid artery using a photochemical reaction. The times to occlusion after the initiation of endothelial injury in all wild type mice was within 12 min, and no significant changes in occlusion delay were observed in uPA-/- and tPA-/- mice compared to wild type mice, whereas that of PAI-1 mice were significantly prolonged (16.9+/-2.9 min, P<0.05). When high molecular weight aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein Ib/V/IX, was administered, the time to occlusion was prolonged in a dose-dependent manner in all types of mice. However, when this compound was injected in tPA-/- mice, the most significant changes were observed: i.e. the estimated ED(50) was 20.2 times higher than that in tPA+/+ mice, but the estimated ED(50) in uPA-/- mice was not changed as compared with that of wild type mice. On the other hand, when ATA was injected in PAI-1-/- mice, the estimated ED(50) was significantly decreased (P<0.05). Platelet aggregation induced by botrocetin was not significantly different among all types of mice. The bleeding time was prolonged in a dose dependent-manner when ATA was injected in all types of mice. In conclusion, the antithrombotic effect of inhibition of platelet GPIb/V/IX is severely affected by the absence or presence of tPA-production on thrombus formation and the inhibition of PAI-1 could enhance this antithrombotic effect.
在组织型纤溶酶原激活物缺陷（tPA-/-）、尿激酶型纤溶酶原激活物缺陷（uPA-/-）或纤溶酶原激活物抑制剂-1缺陷（PAI-1-/-）的小鼠及其野生型对照（tPA+/+、uPA+/+、PAI-1+/+）中，研究了纤溶成分与血小板糖蛋白Ib/V/IX在血栓形成中的相互作用。利用光化学反应在小鼠颈动脉诱导形成血栓。所有野生型小鼠内皮损伤开始后至阻塞的时间在12分钟内，与野生型小鼠相比，uPA-/-和tPA-/-小鼠的阻塞延迟无显著变化，而PAI-1-/-小鼠的阻塞延迟显著延长（16.9±2.9分钟，P<0.05）。当给予血小板糖蛋白Ib/V/IX抑制剂高分子量金精三羧酸（ATA）时，所有类型小鼠的阻塞时间均呈剂量依赖性延长。然而，当将该化合物注射到tPA-/-小鼠中时，观察到最显著的变化：即估计的半数有效剂量（ED50）比tPA+/+小鼠高20.2倍，但与野生型小鼠相比，uPA-/-小鼠的估计ED50没有变化。另一方面，当将ATA注射到PAI-1-/-小鼠中时，估计的ED50显著降低（P<0.05）。所有类型小鼠中由蛇毒巴曲酶诱导的血小板聚集无显著差异。当在所有类型小鼠中注射ATA时，出血时间呈剂量依赖性延长。总之，抑制血小板GPIb/V/IX的抗血栓作用在血栓形成过程中受到tPA产生与否的严重影响，而抑制PAI-1可增强这种抗血栓作用。
