κ阿片受体激动剂U50488H对大鼠心肌缺血再灌注室性心律失常的影响及作用机制  

Effects and mechanisms of U50488H on ventricular arrhythmias induced by myocardial ischemia and reperfusion in rats

作　　者：张鹏[1] 朱运龙[1] 王跃民[1] 李明哲[1] 毕辉[1] 裴建明[1] 

机构地区：[1]第四军医大学基础部生理学教研室

出　　处：《中国临床药理学与治疗学》2006年第3期251-255,共5页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：国家自然科学基金(№30370580);全军医药卫生科研基金军队"十五"计划课题(№01MB129)

摘　　要：目的:研究选择性κ阿片受体激动剂U50488H对大鼠心肌缺血再灌注室性心律失常的影响及作用机制。方法:建立心肌缺血再灌注损伤动物模型,将实验大鼠按随机原则分组,监测大鼠心率(HR)、动脉压(ABP)、左心室内压(LVP)及收缩(+dp/dtmax)和舒张功能(-dp/dtmax)等血流动力学指标,观察大鼠室性心律失常的发生情况和作用机制。结果:U50488H可显著降低大鼠HR、ABP、LVP及±dp/dtmax。在心肌缺血前预先给予U50488H,可明显降低大鼠心肌缺血再灌注室性心律失常的发生率以及室性心律失常评分,该作用可被选择性к阿片受体阻断剂Nor-BNI阻断。提前给予Gi/o蛋白抑制剂pertussis toxin、NO合成酶抑制剂L-NAME、KATP通道阻断剂glibenclamide和PKC的选择性抑制剂chelerythrine,结果发现U50488H的抗心律失常作用减弱(P<0.01);而提前给予TK的抑制剂genistein,对U50488H的抗心律失常作用则无明显影响(P>0.05)。结论:U50488H可通过激动心脏к阿片受体减少大鼠心肌缺血再灌注室性心律失常的发生。在激活к阿片受体前,分别预先阻断Gi/o蛋白P、KC以及KATP通道,可以使к阿片受体介导的抗心律失常的作用减弱或消失,提示к阿片受体的信号转导途径可能涉及Gi/o蛋白P、KC和KATP通道。AIM：To investigate the effects and mechanisms of U50488H （a selective K-opioid receptor agonist） on ventricular arrhythmias induced by myocardial ischemia and reperfusion in rats. METHODS： Rats were randomly divided into different groups respectively. Heart rate （HR）, arterial blood pressure （ ABP ）, left ventricular pressure （LVP）, contractive function （ ＋ dp/dtmax ） and diastolic function （-dp/dtmax） were examined in rots, the incidence of ventricular arrhythmias, ardaythmia score and mechanisms were studied. REULTS： HR, ABP, LVP and ± dp/dtmax in rots were decreased with the administration of U50488H; U50488H intravenously injected before I/R, the incidence of ventricular arrhythmias and arrhythmia score were lowered （P 〈 0.05）. The effect of US0488H was abolished in the presence of Nor-BNI, a selective K-opioid receptor antagonist. Compared with U50488H ＋ I/R group, with the administration of pertussis toxin, glibenclamide and chelerythrine in advance to block the effects of Gi protein,nitrogen oxide synthase, KATP and PKC respectively, the anti-arrhythmic effects induced by κ-opioid receptor in the rats subjected to myocardial ischemia/reperfusion injures were attenuated （P 〈 0.01 ）. While with the disposal of genistein （5 mg.kg^-1, 30 min before U50488H） in advance to block TK, no influence was observed on the anti-arrhythmic effects induced by κ- opioid receptor （ P 〉 0.05）. CONCLUSIONS： κ-opioid receptor stimulation by U50488H elicits the effects of anti-arrhythmia induced by myocardial ischemia and reperfusion. With the administration of pertussis toxin, glibenclamide and chelerythrine to block Gi/o, PKC and KATP respectively in advance, the anti-arrhythmic effects mediated by κ-opioid receptor are weakened or completely abolished （ P 〈 0.01 ） which indicates that Gi/o, PKC and KATP are signal transduction ways of κ-opioid receptor activiation.

关 键 词：U50488H Κ阿片受体 心肌缺血再灌注 心律失常 抑制性G蛋白 蛋白激酶C ATP敏感性钾通道 

分 类 号：R331.3[医药卫生—人体生理学]