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|本期目录/Table of Contents|

U50,488H抗心肌缺血性心律失常与调节钙-Cx43通路有关

《心脏杂志》[ISSN:1009-7236/CN:61-1268/R]

期数:
2012年第5期
页码:
549-558
栏目:
基础研究
出版日期:
2012-10-25

文章信息/Info

Title:
Anti-arrhythmic effect of U50,488H is mediated by preserving Cx43 protein via intracellular calcium regulation
作者:
林家骥; 周 贺; 裴建明
(第四军医大学生理学教研室，陕西 西安 710032)
Author(s):
LIN Jia-ji;  ZHOU He;  PEI Jian-ming
(Department of Physiology, Fourth Military Medical University, Xi’an 710032, Shaanxi, China)
关键词:
心律失常; 心肌缺血;  阿片受体激动剂; 连接蛋白43; SD大鼠; 钙
Keywords:
arrhythmia;  myocardial ischemia;  κ-opioid receptor;  connexin43;  Sprague-Dawley rats;  calcium
分类号:
R331.3
DOI:
-
文献标识码:
A
摘要:
目的:证明κ阿片受体( κ-OR)激动剂(U50,488H)可能是通过调节细胞内钙来保护Cx43蛋白而达到抗心律失常的作用。方法： 在体内心律失常实验中，通过使用丝线短暂阻断成年大鼠冠状动脉左前降支血流30 min。在缺血前由静脉选择注射U50,488H、κ-OR激动剂的阻断剂(or-BNI)、L型钙通道激动剂(Bay K8644)、硝苯地平(Nifedipine)和庚醇(heptanol)。假手术组接受相同的手术过程，但未阻断左前降支血流。在离体心律失常的研究实验中，每个离体心脏被迅速取出，接受10 min的正常灌流后，在37℃下接受30或90 min的实验灌注。实验心脏被分为3个组，即对照组、高钙灌流组及低钙灌流组。实验中，使用心电图(ECG)衡量心律失常的发生率。结果： 对大鼠离体灌流心脏使用心电监测和免疫印迹的实验中显示，高钙灌注的心脏更容易发生心律失常，并检测到Cx43蛋白的表达下调。使用全细胞膜片钳技术观测到U50,488H可以抑制心室细胞的L型钙通道电流。这种现象能并能被nor-BNI所阻断。在心肌缺血损伤之前，注射U50,488H能够提高心律失常的评分。这种现象能并能被nor-BNI、Bay K8644和Cx43蛋白解偶联剂庚醇所阻断。最后免疫印迹的结果证实，U50,488H对Cx43蛋白的保护作用能被Bay K8644所逆转。结论： U50,488H激活κ-OR是通过钙-Cx43信号通路途径发挥抗心律失常的作用。
Abstract:
AIM:To test the hypothesis that antiarrhythmic properties of U50,488H may be mediated by preserving Cx43 protein via regulating intracellular calcium. METHODS: Using an in vivo arrhythmia study, arrhythmia was induced by temporary occlusion of the left anterior descending (LAD) coronary artery with a silk suture for 30 min in Sprague Dawley rats weighing 250 to 350 g. U50,488H, a κ-opioid receptor (κ-OR) agonist, Nor-BNI, a κ-opioid receptor antagonist, Bay K8644, a calcium channel agonist, nifedipine, a calcium channel inhibitor and heptanol, a Cx43 inhibitor were chosen to be intravenously (i.v.) injected into a femoral vein prior to ischemia. A sham group underwent the same surgical procedures except that the suture underneath the LAD was left untied. In an in vitro arrhythmia study, each heart was quickly removed and underwent an initial 10 min of normal baseline perfusion and was subjected to perfusion at 37℃ for 30 min (for analysis of arrhythmia) or 90 min (for Western blotting). The hearts were then randomly divided into three groups: Con (normal calcium perfusion, 1.5 mmol/L), high calcium (high calcium perfusion, 3.3 mmol/L) and low calcium (low calcium perfusion, 0.5 mmol/L). Before and during the ischemia period, electrocardiogram (ECG) was used to measure the incidence of arrhythmias. RESULTS: By performing ECG monitoring and immunoblotting in isolated Langendorff-perfused rat hearts, high concentrations of calcium-perfused rat hearts exhibited increased cardiac arrhythmias. Diminished expression of Cx43 protein was observed. U50,488H dose-dependently inhibited L-type calcium current in single ventricular myocytes of rats using whole-cell patch clamp techniques. These effects were blocked by nor-BNI, a selective κ-OR antagonist. Administration of U50,488H before myocardial ischemia attenuated total arrhythmia scores. This effect was blocked by nor-BNI, antagonized by Bay K8644, an L-type calcium channel agonist, and by the Cx43 uncoupler heptanol. Finally, immunoblotting data demonstrated that the preservation of Cx43 protein conferred by U50,488H was reversed in the presence of Bay K8644. CONCLUSION: κ-OR activation with U50,488H may confer antiarrhythmic effects via modulation of the calcium-Cx43 pathway.

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备注/Memo

备注/Memo:
收稿日期：2012-06-12.
基金项目：国家自然科学基金项目资助(30971060；30770802)
通讯作者：裴建明，教授，主要从事心脏内分泌研究Email:jmpei8@fmmu.edu.cn
作者简介：林家骥，学士Email:timklin@139.com
共同第一作者：周贺，本科生Email:zhouhefmmu@163.com
更新日期/Last Update: 2012-11-16