依达拉奉药物后处理对急性心肌缺血再灌注损伤保护作用的实验研究

Cardioprotective effect of edaravone pharmacological postconditioning on acute myocardial ischemia/ repel-fusion injury： experiment with rats

目的探讨新型自由基清除剂依达拉奉进行药物后处理是否具有减轻心肌缺血再灌注损伤的作用。方法垫扎球囊法建立大鼠急性心肌缺血再灌注模型，给予冠状动脉左前降支缺血45min，再灌注180min。所有动物随机分为6组（每组8只）：（1）假手术组；（2）心肌缺血再灌注组；（3）心肌缺血后处理组；（4）动脉给药1组（依达拉奉3mg／kg主动脉根部给药）；（5）动脉给药2组（依达拉奉10mg／kg主动脉根部给药）；（6）静脉给药组（依达拉奉10mg／kg右股静脉给药）。于再灌注3h末检测血流动力学指标，测定血清肌酸激酶同工酶（CK—MB）及丙二醛（MDA）、超氧化物歧化酶（SOD）活力、一氧化氮（NO）水平，采用伊文思蓝和三苯基氯化四氮唑（TTC）染色的方法确定梗死以及缺血的心肌范围。结果后处理组、动脉给药1组、动脉给药2组的心肌梗死范围比缺血再灌注组（17．2±5．7）％分别减少了54％（8．5±2．4）％、42％（9．9±3．9）％、45％（9．3±4．0）％，CK-MB水平分别降低了59％、55％、58％（P〈0．01），MDA、NO的水平显著降低（均P〈0．01），SOD活力增加（均P〈0．05）。静脉给药组（12．8±5．9）％比缺血再灌注组心肌梗死范围减少了25％，CK-MB水平降低了42％，MDA水平降低，SOD活力增加（P〈0．05）；而NO减少无统计学意义。结论对于急性缺血的心肌，在再灌注前注射依达拉奉进行药物后处理可以减轻心肌缺血再灌注损伤，保护强度与缺血后处理接近，均具有清除活性氧、提高机体抗氧化应激的能力；主动脉根部注射途径可能是一种更加有效的药物后处理方式。

Objective To evaluate the influence of pharmacological postconditioning with edaravone, a new free radical scavenger, on myocardial ischemia/reperfusion injury and the mechanism thereof. Methods Forty Wistar rats underwent ligation of the left anterior descending coronary artery （LAD） with PTCA balloon to establish ischemia/reperfusion models , with the LAD occluded for 45 min and reperfused for 180 min . The rats were randomly divided into 5 equal groups ： （ 1 ） I/R group undergoing occlusion of the LAD for 45 min and reperfusion for 180 min; （2） Ⅰ-postC group undergoing ischemia for 45 min, 3 cycles of balloon air relief-aeration （30s reperfusion and 30s ischemia） , and then reperfusion for 180 min, （3） iA-1 group undergoing injection of edaravone, 3 mg/kg into the aorta root 1 min before reperfusion;（4） iA-2 group undergoing injection of edaravone 10 mg/kg into the aorta root 1 min before reperfusion; and （5） iV group undergoing intravenous injection of edaravone 10 mg/kg 1 min before reperfusion. Another 8 rats underwent sham operation. By the end of experiment arterial blood was collected to measure the dynamic parameters and serum biochemical markers ： MB isoenzyme of creatine kinase （ CK- MB）, malondialdehyde （MDA）, superoxide diamutase （SOD）, and nitric oxide （NO）. Then the rats were killed. The ischemie size and Infarct size of myocardium were measured by Evans blue and TI＇C staining respectively. Results The myocardial infarct size and levels of serum CK-MB, MDA, and NO were all significantly reduced in the Ⅰ-postC, iA-1, and iA-2 groups compared with the I/R group （ all P 〈 0. 01 ）, and the activity levels of SOD of these groups were all enhanced （ all P 〈 0. 05 ）. The MI size and levels of serum CK-MB and MDA of the iV group were all reduced, the activity level of SOD was enhanced compared with the I/R group （ all P 〈 0.05 ） , and the NO level was decreased, but not significantly. Conclusion Edaravone pharmacological postconditioning applied just before the onset of coronary reperfusion provides potent myocardial infarct size reduction, an effect similar to the cardio-protective effect of dynamic postconditioning . The common potential mechanism of both practices may be associated with decreasing the injury by reactive oxygen species and strengthening the resistance to oxidation stress. Intra aorta rootcoronary injection may be a more effective pharmacological postconditioning pathway than intravenous pathway.