κ阿片受体在抗缺血/再灌注大鼠心律失常中的作用机制

Antiarrhythmic effect and underlying mechanism of κ-opioid receptor in rats with myocardial ischemia and reperfusion

目的研究κ阿片受体在抗缺血/再灌注性心律失常中的作用机制,并初步探讨κ阿片受体选择性激动剂U50488H(U50)对大鼠血浆血管紧张素Ⅱ(AngⅡ)、内皮素(ET)和一氧化氮(NO)的调控作用。方法实验大鼠随机分为7组,即对照组(Control),缺血再灌注组(I/R),U50+I/R组,PTX组(pertussis toxin,百日咳毒素,G i/o蛋白抑制剂),G lib组(glibenc lam ide,KATP通道阻断剂),Che组(chel-erythrine,PKC选择性抑制剂)和Gen组(gen iste in,酪氨酸激酶TK抑制剂),观察心律失常发生情况并计算心律失常评分;检测血浆血管紧张素Ⅱ(AngⅡ)、内皮素(ET)和一氧化氮(NO)水平。结果①与I/R组相比,U50488H+I/R组大鼠心律失常评分明显下降,该作用可被选择性κ阿片受体阻断剂nor-BNI阻断。②分别提前给予PTX,glibenc lam ide和chelerythrine后,U50488H的抗心律失常作用可被明显减弱或阻断;③提前给予gen iste in对U50488H的抗心律失常作用无明显影响。④与正常大鼠血浆AngⅡ、ET和NO含量比较,I/R组血浆AngⅡ和ET含量明显增加,NO含量明显降低;给予U50488H处理后,U50+I/R组大鼠血浆AngⅡ和ET含量比I/R组降低,而NO含量则明显升高。结论①κ阿片受体介导了抗缺血/再灌注性心律失常的作用,该作用的信号转导途径可能涉及G i/o、PKC和KATP等通道。②激活κ阿片受体还可能通过下调大鼠血浆AngⅡ和ET或上调NO等因子的水平来发挥抗心律失常作用。

Aim investigate the anti-arrhythmic effect and mechanism of κ-opioid receptor during myocardial ischemia and reperfusion in rats, and to initially determine the regulation of U50488H（ U50, a selective κ-opioid receptor agonist） to angiotensin Ⅱ （Ang Ⅱ ）, endothelin （ET） and nitric oxide （NO） in rats. Methods Rats were randomly divided into 7 groups, i.e., control group, ischemia/reperfusion group （I/ R）, U50488H ＋I/R group, PTX group （PTX, a Gi/o proteininhibitor）, Glib group （glibenclamide, a KATP channel blocker） , Che group （chelerythrine, a selective PKC inhibitor）, and Gen group （Genistein, a Tyrosine kinase inhibitor） respectively. The arrhythmia occurrence and score in different groups were observed and counted. The contents of Ang H , ET and NO in plasma of rats were also examined. Results ① Compared with I/R group, the arrhythmia score of U50 ＋ I/ R group was significantly decreased. The effect of pared with I/R group, the arrhythmia score of U50 ＋ I/R group was significantly decreased . The effect ofglibenclamide and chelerythrine respectively, the antiarrhythmic effects induced by U50488H in the rats during myocardial ischemia and reperfusion were significandy attenuated or even completely blocked. ③ The anti-arrhythmic effects of U50488H were not significandy affected by pretreatment with genistein. ④ In comparison with normal rats, the contents of Ang U and ET in plasma of I/R group were significantly increased, but the content of NO was decreased. With the administration of U50488H, the contents of Ang U and ET in plasma of rats in U50488H ＋ I/R group weresignificantly decreased. Meantime the content of NO was increased. Conclusions ① U50488H-induced anti-arrhythmic effects in the rats with myocardial ischemia ceptor and reperfusion are mediated by κ-opioid receptor. The signaling pathway may be related with Gi/o, PKC, and KATr channel. ② The activation of κ- opioid receptor may elicit anti-arrhythmic effect through the down-regulations of Ang Ⅱ or ET and up-regulation of NO in plasma of rats.