Silver M J, Sutton J M, Hook S, Lee P, Malycky J L, Phillips M L, Ellis S G, Topol E J, Nicolini F A
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Cardiology, Cleveland Clinic Foundation, OH 44195, USA.
Circulation. 1995 Aug 1;92(3):492-9. doi: 10.1161/01.cir.92.3.492.
An adjunctive pharmacological strategy to thrombolytic therapy that is tailored to limit reperfusion injury after thrombolysis could further maximize the unquestioned benefit of restoring flow to ischemic myocardium. Ischemia-reperfusion injury exhibits features characteristic of an acute inflammatory response, including the rapid activation and infiltration of neutrophils. The initial process of neutrophil migration from the circulation to injured tissue is modulated by a group of adhesion molecules called selectins. The purpose of the present study was to assess the efficacy of a selectin blocker (CY 1503) given as an adjunct to thrombolytic therapy to interfere with the inflammatory response after ischemia-reperfusion and subsequently reduce myocardial infarct size in the electrolytic canine model.
A fully occlusive thrombus was formed in the left circumflex coronary artery by electrolytic injury in 20 anesthetized open-chest dogs. After occlusion, an infusion of 1 mg/kg recombinant tissue-type plasminogen activator (rTPA) was administered over 20 minutes with either a bolus of placebo or the selectin blocker CY 1503 (40 mg/kg). At the onset of reperfusion, 20 micrograms/kg per minute rTPA was administered for 1 hour to prevent reocclusion. After 1 hour of reperfusion, infarct size, myocardial myeloperoxidase activity, and reperfusion arrhythmias were measured. In CY 1503-treated dogs, there was a significant 69% reduction in infarct size when expressed as a percentage of the area at risk (6.7 +/- 8.4% versus 21.8 +/- 13.6%; P = .008) and a marked reduction in myeloperoxidase activity (0.014 +/- 0.009 versus 0.0370 +/- 0.025 U/min per gram; P = .02) compared with the placebo group. There was no difference between the groups in the occurrence of reperfusion arrhythmias.
Selectin blockade as an adjunct to rTPA-mediated thrombolysis significantly reduces infarct size and myocardial neutrophil infiltration well beyond thrombolysis alone in the electrolytic canine model. These data suggest that selectin blockade is extremely effective at reducing ischemia-reperfusion injury and myocardial infarct size in this model and that the neutrophil is a potent mediator of ischemia-reperfusion injury.
一种旨在限制溶栓后再灌注损伤的溶栓辅助药物策略，可能会进一步最大限度地发挥恢复缺血心肌血流这一无可争议的益处。缺血再灌注损伤表现出急性炎症反应的特征，包括中性粒细胞的快速激活和浸润。中性粒细胞从循环系统迁移至受损组织的初始过程，受到一组称为选择素的黏附分子的调控。本研究的目的是评估在电解犬模型中，给予选择素阻滞剂（CY 1503）作为溶栓治疗的辅助手段，以干扰缺血再灌注后的炎症反应，并随后减小心肌梗死面积的疗效。
通过电解损伤在20只麻醉开胸犬的左旋冠状动脉中形成完全闭塞性血栓。闭塞后，在20分钟内输注1mg/kg重组组织型纤溶酶原激活剂（rTPA），同时给予一剂安慰剂或选择素阻滞剂CY 1503（40mg/kg）。在再灌注开始时，以每分钟20μg/kg的剂量给予rTPA持续1小时，以防止再闭塞。再灌注1小时后，测量梗死面积、心肌髓过氧化物酶活性和再灌注心律失常。与安慰剂组相比，接受CY 1503治疗的犬，梗死面积以危险区域面积的百分比表示时显著减少69%（6.7±8.4%对21.8±13.6%；P = 0.008），髓过氧化物酶活性显著降低（0.014±0.009对0.0370±0.025U/分钟每克；P = 0.02）。两组在再灌注心律失常的发生方面无差异。
在电解犬模型中，选择素阻断作为rTPA介导的溶栓的辅助手段，显著减小梗死面积和心肌中性粒细胞浸润，其效果远超过单纯溶栓。这些数据表明，在该模型中选择素阻断在减少缺血再灌注损伤和心肌梗死面积方面极其有效，并且中性粒细胞是缺血再灌注损伤的有力介质。
