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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。
OBJECTIVE: To demonstrate that κ-OR agonist (U50,488H) may protect against Cx43 protein by regulating intracellular calcium to achieve antiarrhythmic effect. METHODS: In vivo arrhythmia experiments, the left anterior descending coronary blood flow in adult rats was transiently blocked for 30 min by using silk thread. U50, 488H, κ-OR agonist blockers (or-BNI), L-type calcium channel agonists (Bay K8644), nifedipine, and heptanol were injected intravenously pre- . Sham-operated groups underwent the same surgical procedure but did not block left anterior descending blood flow. In an in vitro arrhythmia study, each isolated heart was promptly removed, subjected to normal perfusion for 10 min and then subjected to 30 or 90 min of experimental perfusion at 37 ° C. Experimental hearts were divided into three groups, namely control group, high calcium perfusion group and low calcium perfusion group. In the experiment, the use of electrocardiogram (ECG) to measure the incidence of arrhythmias. RESULTS: The experiments of electrocardiographic and immunoblotting of perfused heart in vitro showed that cardiac arrhythmia was more likely to occur in high calcium perfusion hearts and the expression of Cx43 protein was down-regulated. Using whole-cell patch-clamp technique, we observed that U50 and 488H could inhibit L-type calcium channel currents in ventricular cells. This phenomenon can and can be blocked by nor-BNI. Prior to myocardial ischemic injury, injection of U50,488H increased the arrhythmia score. This phenomenon can and can be nor-BNI, Bay K8644 and Cx43 protein uncoupler heptanol blocked. The results of the final immunoblotting confirmed that the protective effect of U50,488H on Cx43 protein was reversed by Bay K8644. Conclusion: U50,488H activation kappa-OR is through the calcium-Cx43 signaling pathway to play anti-arrhythmic effect.