沙库巴曲缬沙坦对心肌梗死后心力衰竭大鼠室性心律失常的影响及其机制

Effect and mechanism of sacubitril on ventricular arrhythmias in rats with heart failure after myocardial infarction

目的探究血管紧张素受体-脑啡肽酶抑制剂(angiotensin receptor neprilysin inhibitors,ARNI)沙库巴曲缬沙坦(sacubitril)对心肌梗死后心力衰竭(heart failure,HF)大鼠室性心律失常的影响及其可能机制。方法采用左冠状动脉前降支结扎法制作SD大鼠心肌梗死后心力衰竭模型,随机分成心衰组(HF组)、沙库巴曲缬沙坦组(HF+ARNI组)(68 mg/kg·d^(-1),灌胃)、缬沙坦组(HF+ARB组)(30 mg/kg·d^(-1),灌胃)、MCU抑制剂-钌红组(HF+RR组)(2 mg/kg·d^(-1),腹腔注射)。另设假手术组(Sham组)。连续药物干预4周。药物干预前和结束后行超声心动图检查。开胸burst刺激,检测大鼠室性心律失常诱导率。HE染色观察大鼠心脏组织病理形态学的改变。Western blot法检测大鼠心肌线粒体钙单向转运体(mitochondrial Ca^(2+)uniporter protein,MCU)表达。结果与Sham组相比,HF组大鼠发生心脏结构重构,心功能显著降低(P<0.05)。与HF组、HF+RR组相比,HF+ARNI组大鼠心脏结构重构和心功能显著改善(P<0.05)。与HF+ARB组相比,HF+ARNI组大鼠心脏结构重构显著改善(P<0.05),但是大鼠心功能改善不明显(P>0.05)。与HF组、HF+RR组相比,HF+ARNI组大鼠在电压6V及12V Burst刺激时室性心律失常诱导率显著降低(P<0.05);与HF+ARB组相比,HF+ARNI组大鼠在12V Burst刺激时室性心律失常诱导率显著降低(P<0.05)。Western blot结果示:与Sham组大鼠相比,HF组大鼠心肌中MCU蛋白表达水平显著升高(P<0.05)。与HF组相比,HF+ARNI组大鼠、HF+RR组及HF+ARB组均表现出MCU蛋白表达下降(P<0.05)。与HF+ARB组相比较,HF+ARNI组大鼠心肌MCU表达显著下降(P<0.05)。与HF+ARNI组相比较,HF+RR组大鼠心肌MCU表达下降更显著(P<0.05)。结论ARNI可显著降低心肌梗死后心衰大鼠室性心律失常的诱导率,其机制可能是改善心功能和心脏结构重构,并下调MCU的表达。

Objective To investigate the effect of angiotensin receptor/neprilysin inhibitor(ARNI)on ventricular arrhythmias in rats with heart failure(HF)after myocardial infarction and its possible mechanism.Methods SD rats with heart failure after myocardial infarction were established by ligation of left anterior descending coronary artery,and then divided into heart failure group(HF group),angiotensin receptor/neprilysin inhibitor(ARNI)(HF+ARNI group)(68mg/kg/d,intragastric),valsartan group(HF+ARB group)(30mg/kg/d,intragastric),and mitochondrial Ca^(2+)uniporter protein(MCU)inhibitor-ruthenium red group(HF+RR group)(2mg/kg/d,intraperitoneal injection).The sham operation group(Sham group)was also established.Continuous drug intervention lasted for 4 weeks.Echocardiography was performed before and after drug intervention.The induction rate of ventricular arrhythmia was detected by Burst stimulation.HE staining was used to observe the histopathological changes of rat heart.The expression of MCU in rat myocardium was detected by Western blot.Results Compared with the Sham group,the HF group had cardiac structural remodeling and significantly decreased cardiac function(P<0.05).Compared with HF group and HF+RR group,the cardiac structural remodeling and cardiac function of rats in HF+ARNI group were significantly improved(P<0.05).Compared with HF+ARB group,the cardiac structural remodeling of rats in HF+ARNI group was significantly improved(P<0.05),but the cardiac function of rats in HF+ARNI group was not significantly improved(P>0.05).Compared with HF group and HF+RR group,the induction rate of ventricular arrhythmia in HF+ARNI group was significantly decreased when the voltage was 6V and 12V with the Burst stimulation(P<0.05).Compared with HF+ARB ventricugroup,the induction rate of ventricular arrhythmia in HF+ARNI group was significantly decreased when stimulated with 12V Burst(P<0.05).Western blot results showed that compared with Sham group,the expression level of MCU protein in myocardium of rats in HF group was significantly increased(P<0.05).Compared with HF group,the expression of MCU protein in HF+ARNI group,HF+RR group and HF+ARB group was decreased(P<0.05).Compared with HF+ARB group,the expression of myocardial MCU in HF+ARNI group was significantly decreased(P<0.05).Compared with HF+ARNI group,the expression of myocardial MCU in HF+RR group was significantly decreased(P<0.05).Conclusion ARNI could significantly reduce the induction rate of ventricular arrhythmias in rats with heart failure after myocardial infarction,which might be through improving cardiac function and structural remodeling,and down-regulating the expression of MCU.