缬沙坦后处理对心肌缺血再灌注损伤的保护作用

CARDIOPROTECTIVE EFFECT OF VALSARTAN ON CARDIAC ISCHEMIC-REPERFUSION INJURY

目的了解血管紧张素Ⅱ受体拮抗剂缬沙坦后处理对缺血再灌注心肌细胞凋亡的影响及其机制。方法将24只新西兰大白兔随机分为3组,每组8只。对照组结扎左冠状动脉前降支1 h,再灌注6 h;后处理组结扎左冠状动脉前降支1 h,于再灌注前15 min耳缘静脉注射缬沙坦(30 mg/kg),再灌注6 h;药物干预组结扎左冠状动脉前降支1 h,于再灌注前15 min耳缘静脉注射缬沙坦(30 mg/kg),再灌注前5 min给予蛋白激酶C抑制剂GF109203X(0.05 mg/kg)耳缘静脉注射持续5 min,最后心肌再灌注6 h。处死家兔,取缺血坏死区心肌常规制作石蜡切片,光镜下观察缺血坏死区心肌组织结构的变化,采用Tunel法检测心肌细胞凋亡程度,用免疫组化法检测心肌细胞中Bax和Bcl-2蛋白的表达。结果与对照组和药物干预组比较,后处理组心肌组织结构变化轻微,细胞凋亡指数明显降低(F=4.58,q=3.321、4.001,P<0.01),Bcl-2表达明显增多(F=7.23,q=4.730、4.580,P<0.01),Bax表达明显减少(F=8.35,q=4.684、5.275,P<0.01)。而药物干预组与对照组比较各检测指标差异无显著性(P>0.05)。结论缬沙坦后处理可减少急性缺血再灌注后心肌细胞凋亡,并影响Bcl-2、Bax蛋白的表达,从而对缺血心肌产生保护作用,其保护机制可能与激活蛋白激酶C有关。

Objective To study the effects of valsartan postconditioning an angiotensin 11 receptor antagonist on myocardial apoptosis induced by acute myocardial ischemic-reperfusion, and probe into the probable mechanism. Methods Twenty-four Newzealand rabbits were randomized evenly to three groups： control group, post C group and medicine interventional （MI） group. All rabbits were subjected a total of 60 minutes of left anterior descending coronary artery occlusion （LADO） and 6 hours of reperfusion. In addition, rabbits in post C group received 30 mg/kg i. v. of valsartan 15 minutes before reperfusion. MI group received 30 mg/kg i. v. of valsartan and 0.05 mg/kg i. v. of PKC antagonist GF109203X 15 min and 5 rain before reperfusion, respectively. After the experiment, the rabbits were sacrificed and myocardium tissue obtained for histology. The changes of myocardium morphology was observed microscopically. TUNEL was applied to monitor the myocardium apoptosis. Bcl-2 and Bax protein expressions were assessed by immunohistochemistry. Results Compared with the control and MI, the alteration of myocardium structure in post-C group was very mild and the level of myocardium apoptosis index was reduced significantly （F= 4.58;q=3. 321, 4. 001 ;P〈0.01）. The Bcl 2 protein was significantly increased （F=7.23;q= 4. 730,4. 580;P〈0.01）, while the Bax protein was significantly decreased （F=8.35;q=4. 684,5. 275 ; P〈0.01） in the post-C compared with the other two groups. There was no significant differences in all the index observed between the MI and the control （P〉0.05）. Conclusion Valsartan postconditioning can reduce the myocardium apoptosis and affect the production of Bcl-2 and Bax protein induced by acute myocardial isehemia-reper fusion. Valsartan shows protective effect for ischemic myocardium. The mechanism of protection is probably related to the activation of protein kinase C.