阿片受体激动剂U50,488H通过Cx43介导的抗心律失常作用与抑制钙通道有关  

Anti-arrhythmic effect mediated by regulation of κ-opioid receptor agonist U50,488H on Cx43 is associated with inhibition of calcium channel

作　　者：王微[1] 吴晓东[1] 时全星[2] 樊荣[2] 裴建明[2] 

机构地区：[1]第四军医大学口腔医学系,陕西西安710032 [2]第四军医大学基础部生理学教研室,陕西西安710032

出　　处：《中国药理学通报》2011年第8期1059-1063,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No30971060);国家新药研究基金项目(No2009ZX09301-009-BD11);陕西省自然科学基金资助项目(NoS2011JC5080;S2010SF883)

摘　　要：目的研究U50,488H(选择性κ阿片受体激动剂)是否通过抑制钙通道减少外钙内流参与了κ阿片受体的抗缺血性心律失常作用。方法将30只SD大鼠完全随机设计分为5组(每组6只):对照组(Sham)、缺血组(Isc)、缺血+U50,488H组(Isc+U50)、缺血+U50,488H+钙离子通道激动剂Bay k8644组(Isc+U50+Bay)、缺血+Bay k8644组(Isc+Bay)。建立大鼠急性心肌缺血模型,施行30 min心肌缺血前应用U50,488H(1.5 mg.kg-1)及Bay k8644(66.7μg.kg-1)进行干预,观察各组心律失常发生情况及连接蛋白43(Cx43)在蛋白和基因水平表达的变化。结果①在体动物模型中,Bay k8644可以翻转U50,488H激活κ阿片受体后产生的抗心律失常作用(P<0.05)。②在蛋白表达水平,Bay k8644可以阻断U50,488H对缺血心肌Cx43的保护性上调作用(P<0.01)。③在mRNA表达水平,Bay k8644亦可翻转U50,488H激活κ阿片受体后对缺血心肌Cx43mRNA的调控作用(P<0.01)。结论 U50,488H可通过抑制钙通道减少外钙内流,参与κ阿片受体对缺血心肌Cx43的稳定性调控及抗缺血性心律失常作用。Aim To investigate whether U50,488H（a selective κ-opioid receptor agonist） participates in the anti-arrhythmic effect mediated by κ-opioid receptor through inhibition of calcium channel and reduction of calcium influx.Methods 30 SD rats were randomly divided into 5 groups（6 rats in each group）： control group（Con）,ischemia group（Isc）,ischemia＋U50,488H group（Isc＋U50）,ischemia＋U50,488H＋Bay k8644（a calcium channel activator） group（Isc＋U50＋Bay）,ischemia＋Bay k8644 group（Isc＋Bay）.Models of acute myocardial ischemia were established by ligation of the left anterior descending coronary artery in the rats.U50,488H（1.5 mg·kg-1） and Bay k8644（66.7 μg·kg-1） were administered before the 30 min ischemia.Incidence of arrhythmia,changes of Connexin 43（Cx43） protein and mRNA expression in different groups were observed respectively.Results ① In rat models of acute myocardial ischemia,Bay k8644 reversed the anti-arrhythmic effect mediated by κ-opioid receptor stimulation with U50,488H（P0.05）.② At the level of protein expression,Bay k8644 blocked the protective up-regulation of Cx43 conferred by U50,488H when ischemia occurred（P0.01）.③ At the level of gene expression,Bay k8644 also reversed the stabilization of Cx43 mRNA mediated by κ-opioid receptor stimulation with U50,488H during ischemia（P0.01）.Conclusion Through inhibition of calcium channel and reduction of calcium influx,U50,488H participates in the stabilization of Cx43 and anti-arrhythmic effect mediated by κ-opioid receptor when acute myocardial ischemia occurs.

关 键 词：U50 488H Κ阿片受体 心肌缺血 心律失常 连接蛋白43 钙通道 

分 类 号：R332[医药卫生—人体生理学] R322.11[医药卫生—基础医学]