延迟钠电流在心肌细胞内钙异常介导的心律失常中的作用及其机制

项目名称： 延迟钠电流在心肌细胞内钙异常介导的心律失常中的作用及其机制

项目编号： No.81470454

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 霍勇

作者单位： 北京大学

项目金额： 72万元

中文摘要： 细胞内钙浓度的增高与多种心律失常的触发和折返形成有关，可合并动作电位时程延长，诱发室性心动过速，甚至猝死，临床上常见，治疗困难。多种生理、病理和药物可造成细胞内钙浓度增高。临床小样本的报告证实延迟钠电流抑制剂可抑制包括长QT综合征8在内的钙相关心律失常，根据以往的研究结合预实验的结果我们推测内源性或增强的延迟钠电流在钙相关心律失常发生中起作用。本研究拟在新西兰兔整体心脏和分离的心室肌单细胞水平，应用L型钙通道激动剂Bay-K 8644和异丙肾上腺素制作细胞内钙浓度增高的模型，结合延迟钠电流增强剂、钙调蛋白激酶II和钠钙交换抑制剂重复出细胞内钙增高引起的电生理改变及心律失常，并观察延迟钠电流抑制剂对心室肌动作电位时程、心律失常发生率、钙瞬变、心肌细胞收缩功能的影响，预期结果可证明延迟钠电流与细胞内钙浓度增高发生协同作用，共同促进心律失常的发生，为进一步研究钙相关心律失常的新的治疗方法打下基础

中文关键词： 室性心律失常；钙离子；延迟钠电流；动作电位时程；钙瞬变

英文摘要： An increase in intracellular calcium concentration exists in many physiological, pathological and pharmacological conditions and is associated with triggered activities and reentry mechanisms and arrhythmias which may be related to the prolongation of action potential duration and polymorphic ventricular tachycardias. This kind of calcium-related arrhythmias common in clinic and is hard to be treated. Recent data from a few small clinical studies indicates that late sodium current inhibitors is effective in preventing or reversing the calcium-induced arrhythmias, including long QT syndrome 8. Based on the research results in this laboratory, we speculated that the endogenous or enhanced late sodium current may play a role in the calcium related ventricular arrhythmias, In this study, L-type calcium channel activator Bay-K 8644 and isoproterenol will be used to induce the intracellular overload in the absence and presence of low concentration of late sodium current enhancer ATX-II, NCX inhibitor calmoduline kinase II modulator. Tetrodotoxin (TTX) and ranolazine will be used to inhibit the endogenous or enhanced late sodium current and to reverse the changes in proarrhythmic electrophysilogical factor, and to prevent or treat ventricular arrhythmia and mechanical abnormalities. The results from this study is speculated to confirm the contribution of late sodium current in the calcium-related ventricular arrhythmias and give a new direction on the prevention and treatment of calcium overload related ventricular arrhythmias.

英文关键词： ventricular arrhythmia;calcium ion;late sodium current;action potential duration;calcium transient