卡维地洛对兔扩张型心肌病心肌细胞电重构的影响

Effect of carvedilol on electrical remodeling in rabbit with ADR cardiomyopathy

目的:研究卡维地洛对阿霉素心肌病兔心肌细胞晚期后除极(DADs)和触发活动(TA)发生率的影响,并探讨氧化应激与心肌病电重构之间的关系。方法:40只新西兰大白兔随机分为对照组、阿霉素组、阿霉素+卡维地洛组(卡维地洛组)和阿霉素+倍他乐克组(倍他乐克组),每组10只。建立阿霉素扩张型心肌病模型(阿霉素1mg·kg-1,iv每周两次,共16次)。3周后,对照组和阿霉素组每日以0.9%氯化钠(5ml·kg-1·d-1)灌胃,卡维地洛组和倍他乐克组分别给予卡维地洛(5mg·kg-1·d-1)和倍他乐克(5mg·kg-1·d-1)灌胃,两个月。超声心动图观察各组心脏结构变化,检测血浆中丙二醛(MDA)、谷胱甘肽过氧化酶(GSH-Px)和超氧化物歧化酶(SOD)的浓度,酶解法分离家兔心室肌细胞,应用全细胞膜片钳技术记录动作电位(AP),观察在快频率电刺激下DADs和TA的发生率。结果:与对照组比较,阿霉素组左室舒张末期容积(LVEDV)增大,SOD和GSH-Px降低,MDA增高,左室射血分数(LVEF)降低;与阿霉素组和倍他乐克组比较,卡维地洛组LVEDV缩小,MDA降低,SOD和GSH-Px增加,LVEF增加(均P<0.05);3Hz刺激下,对照组未诱发出DADs和TA,阿霉素组DADs和TA的诱发率显著增加,分别为18/20和11/20(P<0.05);卡维地洛组和倍他乐克组DADs的发生率分别为10/20、16/20,TA的发生率分别为4/20、10/20,两组比较有统计学差异(P<0.05)。结论:阿霉素心肌病兔心肌氧化应激水平增加,心肌细胞电重构,DADs和TA发生率明显增加;卡维地洛降低氧化应激水平,改善心肌细胞电重构,从而降低了DADs和TA的发生。

Objective：To investigate the effect of carvedilol on triggered activity（TA）and delayed afterdepolar- izations（DADs）in cardiac myocytes of rabbits with adriamycin cardiomyopath and the relation between oxidative stress and electrical remodeling in adriamycin cardiomyopath. Method： Forty New Zealand white rabbits were ran- domly divided into four groups （n=10 each）： the control group, the adriamycin group, the carvedilol group and the metoprolol group. Rabbits in the adriamycin group, the metoprolol group and the carvedilol group were intra- venously injected at auri-edge with adriamycin hydrochloride （1 mg · kg-1） twice a week for 8 weeks, and at the same timepoint those in the control group were injected with equal saline. Thereafter, rabbits in the metoprolol group and the carvedilol group were intragastric administrated with metoprolol and carvedilol （5 mg ·kg-1·d-1 ） respectively, and those in the control group and the adriamycin group were intragastric administrated with equal volume of saline. Two months later, left ventricular end diastolic volume（LVEDV）, left ventricular end systolic volume（LVESV） and left ventricular shortening fraction（LVFS） were measured by echocardiogram; MDA, SOD and GSH-Px were mearured. By enzymatic dissociation method, single ventricular myocytes were isolated. Then by whole cell patch clamp technique, action potentials （APs） were recorded. The incidences of delayed afterdepo- larizations （DADs） and triggered activity（TA） were monitored under fast frequency electrical stimulation. Resultl Adriamycin increased MDA, LVEDV and LVESV, and decreased SOD and GSH-Px. And the incidences of DAD sand TA （18/20, 11/20） were significant higher than those in the control group （0/20, 0/20） （P〈0.05）. Carvedilol increased SOD and GSH-Px, decreased MDA, LVEDV and LVESV, and inhibited the increase of incidences of DADs and TA （10/20, 4/20）（P%0.05）. There were no significant different in LVESV,LVEDV and the inci- dences of DADs and TA between the metoproloI group and the adriamyein group. Conelusion..Carvedilol can inhibit the occurrence of DADs and TA in rabbits with adriamycin cardiomyopathy and protect adriamycin-induced cardio- toxicity,which relate to oxygen free radial production.