内源性孤啡肽对大鼠急性心肌缺血引起的心律失常的影响及其机制研究
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摘要
急性心肌梗死引起的严重的室性心律失常已成为造成心源性猝死的主要原因。孤啡肽(nociceptin, Orphanin FQ, OFQ)属于G蛋白耦联受体是神经肽的一种。应用孤啡肽在外周及中枢可均引起程度一定的心率减慢和血压下降,相关研究发现孤啡肽除与参加外周和中枢神经对调节心血管有关外,还可能与其对心血管直接作用有关。本小组前期研究发现,在大鼠急性心肌缺血模型中OFQ表达上调出现在脊髓和背根神经节。提示在急性心肌缺血病理过程中可能有孤啡肽参与,但是对尚不清楚其具体作用机制。心律失常是否由孤啡肽直接调节?需要进一步研究。
目的：研究内源性孤啡肽对急性心肌缺血大鼠心律失常的影响及其可能机制,为临床研究及干预急性心肌缺血病理过程提供新的思路及靶点。
方法：本实验从三个方面进行研究
1.大鼠尾静脉注射孤啡肽受体拮抗剂UFP-101对内源性孤啡肽作用进行在体研究：健康大鼠分为空白对照组(静脉给予生理盐水,C)、不同浓度UFP-101组(1×10-11mol/kg,1×10-9mol/kg and1×10-7mol/kg, U11, U9, U7)。各组尾静脉给药5分钟后开胸结扎冠状动脉,记录分析结扎后一小时心律失常的变化。
2.孤啡肽对心肌细胞的动作电位时程(APD)影响的研究：采用膜片钳技术,急性分离成年SD大鼠心肌细胞,分别用含有不同浓度的OFQ1×10-11mol/L,1×10-9mol/L and1×10-7mol/L,(O11,O9,O7;N=6);OFQ(1×10-9mol/L)+ufp-101(1×10-8mol/L)(O9U8;N=6)和UFP-101(1×10-8mol/L, U8;n=6)的台式液持续灌流心肌细胞对运用全细胞膜片钳模式观察对APD的影响,以探讨孤啡肽对心律失常作用可能的机制。
3.内源性孤啡肽调节急性心肌缺血后室性心律失常发生的作用与PKC通路的关系：利用第一部分实验的心肌标本提取心肌细胞蛋白,采用PKC活性分析试剂盒测定其活化程度；选择UFP-101(1×10-7mol/kg)与PKC拮抗剂Calphostin C (0.1mg/kg)配伍尾静脉给药5分钟后开胸结扎冠状动脉,记录分析结扎后一小时心律失常的变化,以探讨孤啡肽作用可能的分子机制。
结果：
1.与对照组比较,静脉给予UFP-101,能明显降低CAO(急性冠脉结扎)后室性心律失常的发生。从时间分布看,UFP-101对心律失常的作用主要发生在结扎15分钟后。
2.膜片钳实验结果显示,孤啡肽明显缩短心肌细胞APD, UFP-101可以阻断此抑制作用。
3.心肌细胞PKC活性分析显示,UFP-101明显增加PKC活性。静脉给予UFP-101,能明显降低CAO(急性冠脉结扎)后室性心律失常的发生的作用可以被PKC抑制剂所拮抗。
结论：内源性孤啡肽通过缩短动作电位时程或抑制PKC通路促进大鼠急性心肌缺血后室性心律失常的发生
Background—Ventricular arrhythmia has became the primal reson for the people who die fromacute myocardial ischemia[1]. Orphanin FQ (OFQ nociceptin) whose structure primary is similarto dynorphin A indeed is a heptadecapeptide, but has low affinity binds to receptors of opioidclassical[2]. We had found that during acute myocardial ischemia there were more OFQ in pinalcords and dorsal root ganglion of rats [3], which suggest OFQ may participates in this process.Objective---We carried out this study to study the effects of endogenous OFQ on ventriculararrhythmia caused by acute myocardial ischemia in rats and explore the possible mechanism.Methods—The resuarch was devided into three experiments:
1. In this experiment we use adult healthy male SD rats and the weigh of them were250-280g.They were divided into five groups randomly: U11,U9and U7groups were treatment with OFQantagonist compound UFP-101in the dosage of1×10~(-11)mol/kg,1×10~(-9)mol/kg and1×10~(-7)mol/kg, i.v. Calphostin C (0.1mg/kg) a specific inhibitor of PKC and UFP-101(1×10~(-7))mol/kg was administered in U7-C group and the control group were treatment with saline5minbefore they were subjected to the coronary artery occlusion (CAO) for60min and ECG wereobserved and analyzed.
2. We collected the ventricular myocytes from the heart of SD rats.The heart was perfusedwith an solution containing enzyme in Langendorff perfusion. Ventricular myocytes’ actionpotential (AP) was induced and recoded with the technique of whole-cell patch-clamp.Ventricular myocytes were perfused with The Tyrode’s solution contained OFQ in the dosage of1×10~(-11)mol/L,1×10~(-9)mol/L and1×10~(-7)mol/L, i.v.(O11,O9,O7; N=6), UFP-101in the dosageof1×10~(-8)mol/L(U8; n=6) and OFQ (1×10~(-9)mol/L)+ufp-101(1×10~(-8)mol/L)(O9U8; N=6).The effects of OFQ on Action potential duration (APD) were investigated.
3. Study the role of PKC in the process of endogenous Orphanin FQ increases the occurrenceof ventricular arrhythmia caused by acute myocardial ischemia. Peptides were extracted fromthe heart which came from the experiment-1, a detection of PKC with no radioactive was used tomeasure the activity of PKC.Results—7Compared with C group Outbreak number of VEB (ventricular ectopic beats) werelower in U9and U7group P<0.05and can reduce the happening of ventricular tachycardia(VT)and ventricular fibrillation(VF) in U11,U9and U7group P<0.05. Cmopared with U7group theeffect that can drop the happening of ventricular arrhythmia was reversed in U7-C group. The time of ventricular arrhythmia distributed in U11, U9and U7groups was shortter than C group andU7-C groups and the difference mainly in the time of more than15min.8OFQshorted ratventricular myocytes’ APD in O11, O9and O7group obviously P<0.05and UFP-101canreversed the effect of OFQ.9Activity of PKC was higher in U11,U9and U7group comparedwith C group P<0.05.
Conclusion—Endogenous OFQ increases the occurrence of ventricular arrhythmia cauced byCAO in rats which may result from inhibition of APD or PKC-dependent pathway.
目的：研究内源性孤啡肽对急性心肌缺血大鼠心律失常的影响及其可能机制,为临床研究及干预急性心肌缺血病理过程提供新的思路及靶点。
方法：本实验从三个方面进行研究
1.大鼠尾静脉注射孤啡肽受体拮抗剂UFP-101对内源性孤啡肽作用进行在体研究：健康大鼠分为空白对照组(静脉给予生理盐水,C)、不同浓度UFP-101组(1×10-11mol/kg,1×10-9mol/kg and1×10-7mol/kg, U11, U9, U7)。各组尾静脉给药5分钟后开胸结扎冠状动脉,记录分析结扎后一小时心律失常的变化。
2.孤啡肽对心肌细胞的动作电位时程(APD)影响的研究：采用膜片钳技术,急性分离成年SD大鼠心肌细胞,分别用含有不同浓度的OFQ1×10-11mol/L,1×10-9mol/L and1×10-7mol/L,(O11,O9,O7;N=6);OFQ(1×10-9mol/L)+ufp-101(1×10-8mol/L)(O9U8;N=6)和UFP-101(1×10-8mol/L, U8;n=6)的台式液持续灌流心肌细胞对运用全细胞膜片钳模式观察对APD的影响,以探讨孤啡肽对心律失常作用可能的机制。
3.内源性孤啡肽调节急性心肌缺血后室性心律失常发生的作用与PKC通路的关系：利用第一部分实验的心肌标本提取心肌细胞蛋白,采用PKC活性分析试剂盒测定其活化程度；选择UFP-101(1×10-7mol/kg)与PKC拮抗剂Calphostin C (0.1mg/kg)配伍尾静脉给药5分钟后开胸结扎冠状动脉,记录分析结扎后一小时心律失常的变化,以探讨孤啡肽作用可能的分子机制。
结果：
1.与对照组比较,静脉给予UFP-101,能明显降低CAO(急性冠脉结扎)后室性心律失常的发生。从时间分布看,UFP-101对心律失常的作用主要发生在结扎15分钟后。
2.膜片钳实验结果显示,孤啡肽明显缩短心肌细胞APD, UFP-101可以阻断此抑制作用。
3.心肌细胞PKC活性分析显示,UFP-101明显增加PKC活性。静脉给予UFP-101,能明显降低CAO(急性冠脉结扎)后室性心律失常的发生的作用可以被PKC抑制剂所拮抗。
结论：内源性孤啡肽通过缩短动作电位时程或抑制PKC通路促进大鼠急性心肌缺血后室性心律失常的发生
Background—Ventricular arrhythmia has became the primal reson for the people who die fromacute myocardial ischemia[1]. Orphanin FQ (OFQ nociceptin) whose structure primary is similarto dynorphin A indeed is a heptadecapeptide, but has low affinity binds to receptors of opioidclassical[2]. We had found that during acute myocardial ischemia there were more OFQ in pinalcords and dorsal root ganglion of rats [3], which suggest OFQ may participates in this process.Objective---We carried out this study to study the effects of endogenous OFQ on ventriculararrhythmia caused by acute myocardial ischemia in rats and explore the possible mechanism.Methods—The resuarch was devided into three experiments:
1. In this experiment we use adult healthy male SD rats and the weigh of them were250-280g.They were divided into five groups randomly: U11,U9and U7groups were treatment with OFQantagonist compound UFP-101in the dosage of1×10~(-11)mol/kg,1×10~(-9)mol/kg and1×10~(-7)mol/kg, i.v. Calphostin C (0.1mg/kg) a specific inhibitor of PKC and UFP-101(1×10~(-7))mol/kg was administered in U7-C group and the control group were treatment with saline5minbefore they were subjected to the coronary artery occlusion (CAO) for60min and ECG wereobserved and analyzed.
2. We collected the ventricular myocytes from the heart of SD rats.The heart was perfusedwith an solution containing enzyme in Langendorff perfusion. Ventricular myocytes’ actionpotential (AP) was induced and recoded with the technique of whole-cell patch-clamp.Ventricular myocytes were perfused with The Tyrode’s solution contained OFQ in the dosage of1×10~(-11)mol/L,1×10~(-9)mol/L and1×10~(-7)mol/L, i.v.(O11,O9,O7; N=6), UFP-101in the dosageof1×10~(-8)mol/L(U8; n=6) and OFQ (1×10~(-9)mol/L)+ufp-101(1×10~(-8)mol/L)(O9U8; N=6).The effects of OFQ on Action potential duration (APD) were investigated.
3. Study the role of PKC in the process of endogenous Orphanin FQ increases the occurrenceof ventricular arrhythmia caused by acute myocardial ischemia. Peptides were extracted fromthe heart which came from the experiment-1, a detection of PKC with no radioactive was used tomeasure the activity of PKC.Results—7Compared with C group Outbreak number of VEB (ventricular ectopic beats) werelower in U9and U7group P<0.05and can reduce the happening of ventricular tachycardia(VT)and ventricular fibrillation(VF) in U11,U9and U7group P<0.05. Cmopared with U7group theeffect that can drop the happening of ventricular arrhythmia was reversed in U7-C group. The time of ventricular arrhythmia distributed in U11, U9and U7groups was shortter than C group andU7-C groups and the difference mainly in the time of more than15min.8OFQshorted ratventricular myocytes’ APD in O11, O9and O7group obviously P<0.05and UFP-101canreversed the effect of OFQ.9Activity of PKC was higher in U11,U9and U7group comparedwith C group P<0.05.
Conclusion—Endogenous OFQ increases the occurrence of ventricular arrhythmia cauced byCAO in rats which may result from inhibition of APD or PKC-dependent pathway.
引文
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