白藜芦醇对乌头碱诱发大鼠心律失常的预防作用及其可能机制

Preventive effect of resveratrol on arrhythmia induced by aconitine in rats and its potential mechanism

目的探讨白藜芦醇(Res)对乌头碱诱发大鼠心律失常的预防作用及其可能机制。方法取80只大鼠随机分为模型组、模型+Res组、模型+Res+EX-527组、对照组,各20只。模型组和对照组均给予5%羧甲基纤维素钠灌胃,模型+Res组、模型+Res+EX-527组分别给予Res、Res联合EX-527灌胃;两周后,对照组舌下静脉注射生理盐水,其他3组舌下静脉注射乌头碱诱发心律失常。记录各组发生心律失常的大鼠数量、心律失常开始时间,舌下注射后4 min内的Q-T间期、P-R间期、QRS波群宽度和心律失常评分,麻醉前、造模后即刻以及造模后15、30、60 min时各组大鼠心率。造模60 min后处死各组大鼠,观察心肌组织病理学改变,并检测心肌组织中沉默信息调节因子2相关酶1(SIRT1)、腺苷酸活化蛋白激酶(AMPK)、磷酸化AMPK(p-AMPK)、过氧化物酶体增殖物激活受体γ辅助激活因子1α(PGC1α)蛋白表达量。结果(1)模型组、模型+Res+EX-527组、模型+Res组室性心动过速、心室颤动开始时间依次延迟,心律失常评分依次降低;模型+Res组室性心动过速发生率亦低于模型组(均P<0.05)。(2)模型组、模型+Res+EX-527组、对照组、模型+Res组Q-T间期P-R间期依次缩短,QRS波群缩窄(均P<0.05)。(3)随造模时间的延长,模型+Res组心率逐渐降低(P<0.05),而模型组、模型+Res+EX-527组无明显变化(P>0.05);造模后15、30、60 min,模型+Res组心率均低于模型组,而模型+Res+EX-527组心率均高于模型+Res组(均P<0.05)。(4)苏木精-伊红染色结果显示,模型组可见片状心肌嗜伊红染色增强,且呈波浪样变;模型+Res组心肌呈波浪样变,少量点状心肌嗜伊红染色增强;模型+Res+EX-527组心肌组织病变较模型+Res组加重。(5)模型组、模型+Res+EX-527组、对照组、模型+Res组心肌组织SIRT1、p-AMPK、PGC1α蛋白相对表达量依次增加(均P<0.05)。结论Res可对抗乌头碱诱发的大鼠心律失常,其机制可能与激活SIRT1-AMPK-PGC1α信号通路有关。

Objective To investigate the preventive effect of resveratrol(Res)on arrhythmia induced by aconitine and its potential mechanism.Methods Eighty rats were randomly divided into model group(n=20),model+Res group(n=20),model+Res+EX-527 group(n=20)and control group(n=20).The model group and the control group were administrated 5%carboxymethylcellulose sodium by gavage,and the model+Res group and the model+Res+EX-527 group were administrated Res and Res combined with EX-527,respectively,by gavage;two weeks later,injection of normal saline through sublingual vein was conducted in the control group,while injection of aconitine through sublingual vein was conducted in the remaining three groups to induce arrhythmia.Multiple indicators were recorded in each group,including number of rats suffering from arrhythmia,duration for arrhythmia onset,Q-T interval,P-R interval,QRS complex interval and arrhythmia score within four minutes after sublingual injection,as well as heart rates of rats in all groups before anesthesia,immediately after modeling completion and after 15,30 and 60 minutes of modeling.After 60 minutes of modeling,rats were sacrificed in all groups,then the pathological changes in myocardium were observed,besides,the expression of silent information regulator 2 related enzyme 1(SIRT1),adenosine monophosphate activated protein kinase(AMPK),phosphorylated AMPK(p-AMPK)and peroxisome proliferator-activated receptor γ coactivator 1α(PGC1α)proteins was determined in the myocardium.Results(1)Duration of ventricular tachycardia or ventricular fibrillation onset increased,and arrhythmia score declined in the order of the model group,the model+Res+EX-527 group and the model+Res group;the incidence rate of ventricular tachycardia in the model+Res group was lower than that in the model group(all P<0.05).(2)Q-T interval,P-R interval and QRS complex interval decreased in the model group,model+Res+EX-527 group,control group and model+Res group successively(all P<0.05).(3)With the increase of modeling time,heart rate decreased gradually in the model+Res group(P<0.05),but showed little change in the model group and the model+Res+EX-527 group(P>0.05);after 15,30 or 60 minutes of modeling,the model+Res group yielded a lower heart rate compared with the model group,while the rate in the model+Res+EX-527 group was higher than that in the model+Res group(all P<0.05).(4)Hematoxylin-eosin staining results showed that lamellar enhancement of myocardial eosinophilic staining and wave-like change was observed in the model group;wave-like change and a little punctate enhancement of myocardial eosinophilic staining was found in the model+Res group;the myocardial tissue lesions in the model+Res+EX-527 group were more severe than those in the model+Res group.(5)The relative expression of myocardial tissue SIRT1,p-AMPK,and PGC1α proteins increased in the order of the model group,the model+Res+EX-527 group,the control group and the model+Res group(all P<0.05).Conclusion Res can exert an anti-effect on aconitine-induced arrhythmia in rats,and the mechanism may be related to the activation of SIRT1-AMPK-PGC1α signaling pathway.