Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza Str. 2C, 15-222 Bialystok, Poland.
Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2149-57. doi: 10.1161/ATVBAHA.112.253989. Epub 2012 Jul 5.
We compared the antithrombotic effects in vivo of 2 chemically different carbon monoxide-releasing molecules (CORM-A1 and CORM-3) on arterial and venous thrombus formation and on hemostatic parameters such as platelet activation, coagulation, and fibrinolysis. The hypotensive response to CORMs and their effects on whole blood gas analysis and blood cell count were also examined.
CORM-A1 (10-30 µmol/kg, i.v.), in a dose-dependent fashion, significantly decreased weight of electrically induced thrombus in rats, whereas CORM-3 inhibited thrombosis only at the highest dose used (30 µmol/kg). CORM-A1 showed a direct and stronger inhibition of platelet aggregation than CORM-3 in healthy rats, both in vitro and in vivo. The antiaggregatory effect of CORM-A1, but not CORM-3, correlated positively with weight of the thrombus. Concentration of active plasminogen activator inhibitor-1 in plasma also decreased in response to CORM-A1, but not to CORM-3. Neither CORM-A1 nor CORM-3 had an effect on plasma concentration of active tissue plasminogen activator. CORM-3, but not CORM-A1, decreased the concentration of fibrinogen, fibrin generation, and prolonged prothrombin time. Similarly, laser-induced venous thrombosis observed intravitally via confocal system in green fluorescent protein mice was significantly decreased by CORMs. Although both CORM-A1 and CORM-3 (30 µmol/kg) decreased platelets accumulation in thrombus, only CORM-A1 (3-30 µmol/kg) inhibited platelet activation to phosphatidylserine on their surface.
CORM-3 and CORM-A1 inhibited thrombosis in vivo, however CORM-A1, which slowly releases carbon monoxide, and displayed a relatively weak hypotensive effect had a more pronounced antithrombotic effect associated with a stronger inhibition of platelet aggregation associated with a decrease in active plasminogen activator inhibitor-1 concentration. In contrast, the fast CO releaser CORM-3 that displayed a more pronounced hypotensive effect inhibited thrombosis primarily through a decrease in fibrin generation, but had no direct influence on platelet aggregation and fibrynolysis.
我们比较了两种化学结构不同的一氧化碳释放分子（CORM-A1 和 CORM-3）在体内抗血栓形成的效果，以及对血小板激活、凝血和纤溶等止血参数的影响。还研究了 CORMs 的降压反应及其对全血气体分析和血细胞计数的影响。
CORM-A1（10-30 μmol/kg，静脉注射）以剂量依赖的方式显著降低大鼠电诱导血栓的重量，而 CORM-3 仅在使用的最高剂量（30 μmol/kg）时抑制血栓形成。CORM-A1 在健康大鼠体内和体外均表现出直接且更强的抑制血小板聚集作用，而 CORM-3 则不然。CORM-A1 的抗聚集作用，而不是 CORM-3，与血栓的重量呈正相关。血浆中活性纤溶酶原激活物抑制剂-1的浓度也因 CORM-A1 而降低，但不是因 CORM-3。CORM-A1 或 CORM-3 均未影响血浆中活性组织型纤溶酶原激活物的浓度。CORM-3 降低纤维蛋白原浓度、纤维蛋白生成并延长凝血酶原时间，但 CORM-A1 则不然。同样，通过 GFP 小鼠体内共聚焦系统观察到的激光诱导静脉血栓形成也显著减少。尽管 CORM-A1 和 CORM-3（30 μmol/kg）均减少血栓中血小板的积聚，但只有 CORM-A1（3-30 μmol/kg）抑制血小板表面的磷脂酰丝氨酸的激活。
CORM-3 和 CORM-A1 抑制体内血栓形成，但 CORM-A1 缓慢释放一氧化碳，且降压作用相对较弱，具有更明显的抗血栓形成作用，与更强的抑制血小板聚集作用相关，同时与活性纤溶酶原激活物抑制剂-1浓度降低相关。相比之下，快速 CO 释放剂 CORM-3 具有更明显的降压作用，主要通过降低纤维蛋白生成来抑制血栓形成，但对血小板聚集和纤溶没有直接影响。
