κ-阿片受体激动剂U50488H对内皮素-1所致大鼠室性心律失常的影响

Effect of κ-opioid receptor agonist U50488H on ventricular arrhythmias induced by ET-1 in rats

目的:研究κ-阿片受体选择性激动剂U50488H是否可通过调节内皮素-1(ET-1)表达的水平,进而影响c-Src蛋白酪氨酸激酶(PTK)的表达以实现抗心律失常的作用。方法:将42只大鼠随机分为7组(每组6只):正常对照组、U50488H组、U50488H+nor-BNI组、nor-BNI组、ET-1组、ET-1+U50488H组及ET-1+U50488H+nor-BNI组。左心室及股动脉插管观测大鼠心率(HR)、动脉压(ABP)、左心室内压(LVP)及心脏收缩和舒张功能(±LVdp/dtmax)等血流动力学指标,并计算大鼠室性心律失常的发生情况和大鼠的死亡率。实时荧光定量PCR检测ET-1及ET-1受体(ETRA)mRNA表达;Western blot测定ETRA及下游分子c-Src PTK的表达水平。结果:U50488H可显著抑制ET-1所致大鼠ABP、LVP以及心脏收缩、舒张功能的升高,并可显著降低ET-1所致大鼠室性心律失常的发生率和死亡率(P<0.01),以及抑制心肌ET-1 mRNA的水平(P<0.01)。给予ET-1后,磷酸化(P)-c-Src PTK的表达水平升高,U50488H可显著降低c-Src PTK的水平以及ET-1引起的P-c-Src PTK表达的水平(P<0.05),此作用可被κ-阿片受体阻断剂nor-BNI所阻断。结论:κ-阿片受体选择性激动剂U50488H可抑制ET-1所致大鼠室性心律失常发生。该作用可能与抑制ET-1及其下游分子c-Src PTK的表达有关。

AIM： To investigate the effect of κ-opioid receptor agonist U50488H on arrhythmia induced by endothelin-1（ET-1） and the underlying mechanism.METHODS： Rats were randomly divided into seven groups（six rats in each group）： control group,U50488H group,U50488H＋nor-BNI（a selective κ-opioid receptor antagonist） group,nor-BNI group,ET-1 group,ET-1＋U50488H group and ET-1＋U50488H＋nor-BNI group.Heart rate（HR）,arterial blood pressure（ABP）,left ventricular pressure（LVP）,systolic function（＋LVdp/dtmax） and diastolic function（-LVdp/dtmax） were examined.Arrhythmia score and mortality were determined and expressions of ET-1,ET-1 recepter（ETRA）,and c-Src protein tyrosine kinase were assessed.RESULTS： U50488H significantly attenuated the increase in ABP,LVP and ±LVdp/dtmax and reduced the incidence of ventricular arrhythmias and animal mortality induced by ET-1（P〈0.01）.U50488H also downregulated myocardial ET-1 mRNA（P〈0.01） and c-Src protein tyrosine kinase expressions（P〈0.05）.In addition,ET-1 stimulated phosphorylation of c-Src protein tyrosine kinase,which was reversed by U50488H（P〈0.05）.The effect of U50488H was abolished by nor-BNI,a selective κ-opioid receptor antagonist.CONCLUSION： κ-opioid receptor agonist U50488H reduces ET-1 induced arrhythmia.Effects may be related to the inhibition of the expression of ET-1 and its downstream molecule c-Src protein tyrosine kinase.