异丙酚对大鼠离体心脏缺血再灌注损伤的保护作用及其机制

Protective effect and mechanism of propofol on ischemia/reperfusion injury in the isolated rat heart

目的:考察异丙酚对大鼠离体心肌缺血再灌注的影响及蛋白激酶C(PKC)激活在其中的作用。方法:应用Langendorff离体心脏灌注系统建立心肌缺血再灌注损伤模型。大鼠随机分为正常对照组、缺血再灌注(I/R)模型组、异丙酚低、中、高剂量(15,30,60μmol/L)组和异丙酚(60μmol/L)和PKC抑制剂白屈菜红碱(chelerythrine,5μmol/L)组。除正常对照组外,各组分别平衡灌注20 min后,常温全心停灌25 min,再灌注30 min,记录各组平衡末、缺血前及再灌30 min时心率(HR)、左室收缩压(LVSP)、左室舒张末压(LVDEP)、左室压力变化速率(±dp/dtmax)、冠脉流量(CF)等心功能指标;测定冠脉流出液中乳酸脱氢酶(LDH)、磷酸肌酸激酶(CK)活性;透射电镜观察心肌细胞超微结构变化。差速离心提取心肌线粒体,测定线粒体超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)、ATP酶活性和丙二醛(MDA)含量。结果:异丙酚中、高剂量组能有效减轻缺血再灌注引起的左室功能下降,降低冠脉流出液中LDH、CK的活性(P<0.05);心肌细胞超微结构显示线粒体损伤明显减轻;增强心肌线粒体中SOD、GSH-PX活性、减少MDA的生成(P<0.05),提高线粒体ATP酶活性(P<0.05)。白屈菜红碱能部分减弱异丙酚的心肌保护作用。结论:异丙酚对大鼠离体心肌缺血再灌注损伤有保护作用,这可能与其抗脂质过氧化和激活PKC有关。

Aim： To investigate the effect of propofol on ischemia-reperfusion （I/R） injury in the isolated rat heart model and exploit the relation of the activation of protein kinase C（PKC） to the observation. Methods：The Langen-dorff model of ischemia-reperfusion was used. 48 isolated rats （used to establish isolated perfused rat heart model） were divided into control group, I/R group, propofol 15, 30, 60μmol/L group, and propofol 60 μmol/L ＋ chelerythrine （PKC inhibitor） 5 μmol/L group. Except the control, the hearts were subject to 25-min global ischemia and then 30-min reperfusion. The cardiac function indexes such as the left ventricular systolic pressure （LVSP）, the left ventricular end diastolic pressure （LVDEP）, heart rate （HR）, and coronary arterial flow （CF） were recorded at the times of equilibration, prior to ischemia, and the end of reperfusion, respectively. The activities of lactate dehydrogenase （LDH） and creatine kinase （CK） in the effluents were measured. The pathological changes to myocardium were observed by transmission electron microscope. The activities of SOD, GSH-PX, ATPase and the amounts of malondialdehyde （MDA） in myocardial mitochondrion during the reperfusion were measured. Results： Exposure to propofol at 30 and 60 μmol/L significantly ameliorated the CF, LVDP and LVDEP（ P 〈 0.05）, and significanthy reduced the activities of the LDH and CK in the effluents（ P 〈 0.05）and the amounts of MDA in myocardial mitochondrion（ P 〈 0.05）. In comparison to I/R group, the exposure also significantly enhanced the activities of SOD, GSH-PX and ATPase（ P 〈0.05）. The histopathological changes to mitochondrion and myocardium induced by I/R were also markedly alleviated. Chelerythrine （5 μmol/L） partly suppressed the improvement in the cardiac functions associated with propofol （60 μmol/L）. Conclusion： It might be concluded that propofol administrered prior to the ischemia and during the reperfusion has beneficial cardioprotective effects on the I/R injury in the isolated rat heart. The mechanism might be related to the activation of protein kinase C before ischemia and in turn the inhibition of lipid peroxidation, thus reducing oxidative stress during the repeffusion.