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

中国临床药理学与治疗学 ›› 2006, Vol. 11 ›› Issue (3): 251-255.

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

张鹏, 朱运龙, 王跃民, 李明哲, 毕辉, 裴建明

第四军医大学基础部生理学教研室,西安 710033,陕西

收稿日期:2005-11-25 修回日期:2006-01-19 出版日期:2006-03-26 发布日期:2020-12-04
通讯作者: 裴建明,男,教授,博士生导师,生理学博士、博士后,主要研究脏器缺血再灌注损伤。Tel:029-83374519 E-mail:Jmpei8@fmmu.edu.cn
作者简介:张鹏,男,主治医师,讲师,生理学博士,从事肾脏病博士后科研工作。Tel:(0)1385151539 E-mail:pengpengpeng-zh@163.com
基金资助:
国家自然科学基金(No30370580);全军医药卫生科研基金军队“十五”计划课题(No01MB129)

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

ZHANG Peng, ZHU Yun-long, WANG Yue-min, LI Ming-zhe, BI Hui, PEI Jian-ming

Department of Physiology,School of Basic Medicine,Fourth Military Medical University,Xi'an 710033,Shannxi,China

Received:2005-11-25 Revised:2006-01-19 Online:2006-03-26 Published:2020-12-04

摘要/Abstract

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/dt_max)和舒张功能(-dp/dt_max)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/dt_max。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pertussistoxin、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、PKC以及K_ATP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、PKC和K_ATP通道。

关键词: U50488H, к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

Abstract: AIM: To investigate the effects and mechanisms of U50488H (a selectiveк-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/dt_max) and diastolic function (-dp/dt_max) were examined in rats,the incidence of ventricular arrhythmias,arrhythmia score and mechanisms were studied.RESULTS: HR,ABP,LVPand±dp/dt_max in rats 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 U50488H was abolished in the presence of Nor-BNI,a selectiveк-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,KATPand PKC respectively,the anti-arrhythmic effects induced byκ-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 byκ-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 KATPrespectively in advance,the anti-arrhythmic effects mediated byκ-opioid receptor are weakened or completely abolished (P<0.01) which indicates that Gi/o,PKC and K_ATP are signal transduction ways ofκ-opioid receptor activiation.

Key words: к-opioid receptor, myocardial ischemia/reperfusion injury, arrhythmia, Gi protein, protein kinase C, K_ATP channel

中图分类号:

R331.3

张鹏, 朱运龙, 王跃民, 李明哲, 毕辉, 裴建明. 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[J]. 中国临床药理学与治疗学, 2006, 11(3): 251-255.

参考文献

1 GalinnanesM,Fowler AG.Role of clinical pathologies in myocardial injury following ischemia and reperfusion[J].Cardiaovasc Res,2004;61:512-21
2 Piper HM,Abdollah Y,Schafer C.The first minutes of reperfusion:a window of opportunity for cardioprotection[J].Cardiaovasc Res,2004;61:365-71
3 Hilchen TS,Knut AK.Preconditioning-endogenous defence mechanism of the heart[J].ACTA Anaesthesiol Scand,2002;46:123-37
4 Coles JJA,Sigg DC,Iaizzo PA.The Role of Kappa-Opioid Receptor Activation in Pharmacological Preconditioning of Swine[J].Am J Physiol Heart Circ Physiol,2003;284:H2091-9
5 Yu XC,Wang HX,Pei JM,Wong TM.Anti-arrhythmic effect ofкopioid receptor stimulation in the perfused rat heart:Involvement of a cAMP-dependent pathway[J].J Mol Cell cardiol,1999;31:1809-19
6 Schultz JE,Hsu AK,Gross GJ.Morphine mimics the cardioprotective effect of ischemic preconditioning via a glibenclamide-sensitive mechanism in the rat heart[J].Circ Res,1996;78:1100-4
7 Curtis M,Walker MJ.Quantification of arrhythmias using scoring systems:an examination of seven scores in an vivo model of regional myocardial ischemia[J].Br J Pharmacol,1988;22:656-65
8 Chen M,Zhou JJ,Kan KW,Qi JS,YanWY,Wu S,et al.Roles of KATP channels in delayed cardioprotection and intracellular Ca2+in the rat heart as revealed by kappa-opioid receptor stimulation with U50488H[J].Br J Pharmacol,2003;140:750-8
9 Horimoto H,Gaudette GR,Saltman AE,Krukenkamp IB.The role of nitric oxide,K+_ATP channels,and cGMP in the preconditioning response of the rabbit[J].J Surg Res,2000;92:56-63
10 Suematsu Y,Ohtsuka T,Hirata Y,Maeda K,Imanaka K,Takamoto S.L-Arginine given after ischaemic preconditioning can enhance cardioprotection in isolated rat hearts[J].Eur J Cardiothorac Surg,2001;19:873-9
11 Schulz R,Kelm M,Heusch G.Nitric oxide in ischemia-reperfusion injury[J].Cardiaovasc Res,2004;61:402-13
12 张鹏,裴建明,王跃民,朱运龙,李明哲.U50488H 对缺血再灌注大鼠血流动力学和心肌超微结构的影响[J].第四军医大学学报,2003;24:1275-8
13 张鹏,朱运龙,王跃民,李明哲,毕辉,裴建明.к阿片受体选择性激动剂U50488H 对大鼠心脏功能的影响[J].中国临床康复,2004;8:3495-6

[1]	张华斌, 罗中旭, 钟民, 洪宗元, 王德国. 脊髓麻醉对大鼠急性心肌缺血再灌注室性心律失常的影响研究[J]. 中国临床药理学与治疗学, 2023, 28(3): 249-256.
[2]	华海燕, 严杰, 秦宇芬. 五味子乙素通过抑制心肌细胞凋亡减轻大鼠心肌缺血再灌注损伤的实验研究[J]. 中国临床药理学与治疗学, 2022, 27(8): 848-856.
[3]	徐润泽, 韩静静, 李文倩, 杨劲. 从非临床到临床心律失常风险阶段评估体系研究进展[J]. 中国临床药理学与治疗学, 2021, 26(4): 423-433.
[4]	陈树儒, 路荣忠, 杜冠华, 赵玉军, 杨新博. 天然心房肽抗心律失常病例报道与机制分析[J]. 中国临床药理学与治疗学, 2021, 26(10): 1213-1214.
[5]	陈力方, 王博, 王维蓉. 组蛋白去乙酰化酶3在心血管疾病中的研究进展[J]. 中国临床药理学与治疗学, 2021, 26(1): 88-97.
[6]	吴娟，张鹤，冯桂林. 蛇毒血小板抑制因子对心肌缺血再灌注损伤大鼠血小板膜糖蛋白VI表达以及血液流变的影响及意义[J]. 中国临床药理学与治疗学, 2020, 25(1): 49-54.
[7]	王荣俊，丁波. 人urotensinⅡ对大鼠心肌缺血缺氧性损伤的保护作用机制[J]. 中国临床药理学与治疗学, 2017, 22(6): 622-626.
[8]	蒙国懿，何繁漪，隋念含，赵林波，洪仕君，邢豫明，赵永娜. RGS4和D2受体信号通路相关分子在甲基苯丙胺依赖CPP大鼠纹状体的表达变化[J]. 中国临床药理学与治疗学, 2017, 22(12): 1377-1381.
[9]	吴彤，单颖. 牛磺酸对心肌缺血再灌注大鼠模型心肌损伤的保护作用[J]. 中国临床药理学与治疗学, 2016, 21(8): 884-889.
[10]	何胜虎，周胜华，张晶,王雪飞,王大新. 急性ST段抬高型心肌梗死急诊PCI发生恶性心律失常临床特点及替罗非班的影响[J]. 中国临床药理学与治疗学, 2016, 21(4): 432-435.
[11]	宗巧凤, 程向阳, 于影, 张蔚屏, 高琴, 李正红. 内啡肽-1后处理对大鼠心肌缺血再灌注损伤的实验研究[J]. 中国临床药理学与治疗学, 2015, 20(2): 132-137.
[12]	后承林, 周炜, 卿恩明, 张铁铮, 刘功俭, 容俊芳, 武庆平, 郭曲练, 艾登斌, 金孝岠. 兰地洛尔治疗手术期心动过速性心律失常的多中心疗效和安全性评价[J]. 中国临床药理学与治疗学, 2015, 20(10): 1131-1136.
[13]	焦浩, 童旭辉, 董淑英, 谷昱琛, 余彬彬, 于丽. 缝隙连接在缺血后处理保护大鼠脑缺血再灌注损伤中的作用及可能机制[J]. 中国临床药理学与治疗学, 2014, 19(8): 841-845.
[14]	张凤云, 赵炎, 吴玉林. 蛋白激酶C在脑缺血再灌注损伤中的作用[J]. 中国临床药理学与治疗学, 2013, 18(4): 461-468.
[15]	万星, 石刚刚. 钙非依赖磷脂酶A₂与心肌缺血再灌注关系的研究进展[J]. 中国临床药理学与治疗学, 2013, 18(11): 1304-1309.