Experimental Animal Laboratory, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Thromb Haemost. 2010 Sep;104(3):609-17. doi: 10.1160/TH09-12-0823. Epub 2010 Aug 5.
Reperfusion therapy for myocardial infarction is limited by significant re-occlusion rates and less-than-optimal myocardial tissue perfusion. It was the objective of this study to assess and compare the effect of ticagrelor, the first reversibly binding oral P2Y12 receptor antagonist, with that of clopidogrel, in conjunction with thrombolytic therapy, on platelet aggregation, thrombus formation, and myocardial perfusion in a canine model. Thrombus formation was induced by electrolytic injury and blood flow was measured with a Doppler ultrasonic flowmeter. All animals received tissue plasminogen activator (tPA) (1 mg/kg over 20 min); 10 animals received clopidogrel (10 mg/kg IV bolus over 5 min), 10 animals received ticagrelor initiated with a 1-min bolus (75 microg/kg/min), followed by continuous infusion (10 microg/kg/min) for 2 h, and 10 animals received IV saline. Re-occlusion rate and cyclic flow variation decreased with ticagrelor compared to saline groups (p<0.05). Adenosine phosphate (ADP)-induced platelet aggregation decreased with ticagrelor (1.9% +/- 2.67) and clopidogrel (1.11% +/- 2.0) vs. saline (26.3% +/- 23.5, p<0.05) at the end of adjunctive therapy. Bleeding time increased in the clopidogrel compared to the ticagrelor group (p=0.01). Infarct size was reduced with ticagrelor compared to the clopidogrel and saline groups (p<0.05). Blood flow remained significantly below baseline values at 20 min after tPA administration in the saline and clopidogrel groups but not in the ticagrelor group. In conclusion, in a dog coronary thrombosis model, ticagrelor blocks ADP-induced platelet activation and aggregation; prevents platelet-mediated thrombosis; prolongs reperfusion time and reduces re-occlusion and cyclic flow variation; and significantly decreases infarct size and rapidly restores myocardial tissue perfusion.
心肌梗死的再灌注治疗受到再闭塞率高和心肌组织灌注不理想的限制。本研究旨在评估和比较替格瑞洛（一种可逆转结合的口服 P2Y12 受体拮抗剂）与氯吡格雷联合溶栓治疗对犬模型中血小板聚集、血栓形成和心肌灌注的影响。血栓形成通过电解损伤诱导，血流通过多普勒超声流量计测量。所有动物均接受组织型纤溶酶原激活物（tPA）（20 分钟内 1 毫克/千克）；10 只动物接受氯吡格雷（5 分钟内静脉推注 10 毫克/千克），10 只动物接受替格瑞洛，首先静脉推注 1 分钟（75 微克/千克/分钟），然后连续输注（10 微克/千克/分钟）2 小时，10 只动物接受静脉生理盐水。与盐水组相比，替格瑞洛组的再闭塞率和循环流量变化减少（p<0.05）。ADP 诱导的血小板聚集在替格瑞洛组（1.9% +/- 2.67）和氯吡格雷组（1.11% +/- 2.0）中减少，而在辅助治疗结束时在盐水组中增加（26.3% +/- 23.5，p<0.05）。与替格瑞洛组相比，氯吡格雷组的出血时间增加（p=0.01）。与氯吡格雷组和盐水组相比，替格瑞洛组的梗死面积减少（p<0.05）。在 tPA 给药后 20 分钟，替格瑞洛组的血流仍明显低于基线值，而在盐水组和氯吡格雷组则没有。总之，在犬冠状动脉血栓模型中，替格瑞洛可阻断 ADP 诱导的血小板激活和聚集；防止血小板介导的血栓形成；延长再灌注时间，减少再闭塞和循环流量变化；并显著减少梗死面积并迅速恢复心肌组织灌注。
