Department of Physiology, MSB 3050, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Cardiovasc Drugs Ther. 2013 Apr;27(2):109-15. doi: 10.1007/s10557-012-6436-7.
Recent studies in rabbits have demonstrated that platelet P2Y12 receptor antagonists are cardioprotective, and that the mechanism is surprisingly not related to blockade of platelet aggregation but rather to triggering of the same signal transduction pathway seen in pre- and postconditioning. We wanted to determine whether this same cardioprotection could be documented in a primate model and whether the protection was limited to P2Y12 receptor antagonists or was a class effect.
Thirty-one macaque monkeys underwent 90-min LAD occlusion/4-h reperfusion.
The platelet P2Y12 receptor blocker cangrelor started just prior to reperfusion significantly decreased infarction by an amount equivalent to that seen with ischemic postconditioning (p < 0.001). For any size of risk zone, infarct size in treated hearts was significantly smaller than that in control hearts. OM2, an investigational murine antibody against the primate collagen receptor glycoprotein (GP) VI, produced similar protection (p < 0.01) suggesting a class effect. Both cangrelor and OM2 were quite effective at blocking platelet aggregation (94 % and 97 %, respectively).
Thus in a primate model in which infarct size could be determined directly platelet anti-aggregatory agents are cardioprotective. The important implication of these investigations is that patients with acute myocardial infarction who are treated with platelet anti-aggregatory agents prior to revascularization may already be in a postconditioned state. This hypothesis may explain why in recent clinical trials postconditioning-mimetic interventions which were so protective in animal models had at best only a modest effect.
最近在兔子身上的研究表明，血小板 P2Y12 受体拮抗剂具有心脏保护作用，而其作用机制令人惊讶的与血小板聚集抑制无关，而是与预处理和后处理中所见的相同信号转导途径的触发有关。我们想确定这种相同的心脏保护作用是否可以在灵长类动物模型中得到证实，以及这种保护作用是否仅限于 P2Y12 受体拮抗剂，或者是否具有类效应。
31 只猕猴进行了 90 分钟的 LAD 闭塞/4 小时再灌注。
在再灌注开始前给予血小板 P2Y12 受体阻滞剂坎格雷洛显著减少了梗塞的发生，其效果相当于缺血后处理（p < 0.001）。对于任何大小的危险区域，治疗组心脏的梗塞面积明显小于对照组。OM2 是一种针对灵长类动物胶原蛋白受体糖蛋白（GP）VI 的实验性鼠抗体，也产生了类似的保护作用（p < 0.01），表明具有类效应。坎格雷洛和 OM2 均能有效抑制血小板聚集（分别为 94%和 97%）。
因此，在一种可以直接确定梗塞面积的灵长类动物模型中，血小板抗聚集剂具有心脏保护作用。这些研究的重要意义在于，在血管再通前接受血小板抗聚集剂治疗的急性心肌梗死患者可能已经处于后处理状态。这一假设可以解释为什么在最近的临床试验中，在动物模型中如此保护性的后处理模拟干预措施的效果最好只有适度的效果。
