孤啡肽受体拮抗剂抑制大鼠急性心肌缺血后心律失常的机制研究

Ventricular arrhythmia has became the primal reson for the people who die from acute myocardial ischemia. Current study has found that antagonism of endogenous N/OFQ action produces anti-arrhythmic effects on the infarction-associated ventricular arrhythmias, possibly via modulating PKC activity and action potential of myocytes. But the potential molecular mechanisms were not investigated. The study will focus on investigation of (1) Whether the action that N / OFQ receptor antagonists inhibit the arrhythmia after acute myocardial ischemia associated with the sympathetic nervous system; (2) The effect of N / OFQ on several ion channels Ito, ICa-L and IK1 which play the main role in the Process of repolarization. Further explore the mechanisms regulating electrical activity from the genetic and molecular level; (3)To study the mechanism of N / OFQ receptor antagonists inhibit the arrhythmia caused by acute myocardial ischemia; (4)Cardiac electrophysiology will be observed after the expression of N / OFQ receptor was upregulated by transgenic cells. Explore more effective methods of myocardial protection and clinical treatments for early prevention and treatment of acute myocardial ischemia-induced arrhythmias provide therapeutic targets.

急性心肌梗死（MI ）引起的室性快速性心律失常是心源性猝死的主要原因。本课题组研究发现，内源性孤啡肽受体拮抗剂通过调节PKC活性及动作电位时程抑制大鼠急性心肌缺血引起的心律失常的发生。但是调节的具体分子机制还不明确。本研究通过建立大鼠急性心肌缺血模型，观察（１）N / OFQ受体拮抗剂抑制急性心肌缺血后心律失常发生的作用是否与交感神经系统有关联或存在相互作用；（２）N / OFQ对大鼠心肌细胞动作电位复极化贡献最大的几种离子通道Ito、ICa-L 和IK1的影响，并从基因和分子水平进一步探索其调节电生理活动的机制；（３）N / OFQ受体拮抗剂抑制大鼠急性心肌缺血引起的心律失常发生的机制;（４）通过转基因上调N/OFQ受体表达观察心肌细胞电生理变化。探索更有效的心肌保护方法和临床治疗方法，为早期防治急性心肌缺血引起的心律失常提供治疗靶点。