关白附中hetisine 型生物碱选择性阻断Na+/K+离子通道的作用机制和构效关系研究

心律失常是临床上常见且极具危险性的心血管疾病，突发性恶性心律失常会诱发心源性猝死，严重威胁生命。心肌细胞膜离子通道在心律失常的病理生理发展过程中起着非常关键的作用，目前临床常用的抗心律失常药物通常是作用于心肌细胞膜离子通道，但在治疗过程中较易产生致心律失常的副作用。因此，寻找安全的新型离子通道阻断剂仍是抗心律失常药物研发的重要方向。在前期工作中，本课题组首次从关白附中发现了一系列具有复合型K+通道阻断作用的hetisine型生物碱，且连有不同取代基团的hetisine型生物碱可呈现出对Na+/K+通道的选择性阻断作用。本项目拟在前期工作基础上，进一步系统分离和富集关白附中的hetisine型生物碱，对其抗心律失常活性进行评价，并探讨该类生物碱选择性阻断Na+/K+通道的作用机制及构效关系，为研究和开发安全、有效的抗心律失常药物提供科学依据。

Arrhythmia is a extremely dangerous clinical cardiovascular disease, it is serious life-threatening that unexpected malignant arrhythmia could be induced to sudden cardiac death.Cardiac myocyte ion channels plays a very key role in the pathophysiology of the arrhythmia diseases, clinical medicine treat arrhythmias by way of blocking the ion channels in myocardial cell, however it is prone to arrhythmogenic effect in the process. Therefore, the research and development of a new security the ion channel blockers is an important direction for antiarrhythmic drug. In the previous active ingredients research, we found a series of complex K+channel blocking activity of hetisine type alkaloids from aconitum coreanum for the first time, and different substituent groups of hetisine type alkaloids showing selective blocking of Na+ or K+channel. The project is based on previous work, further isolation and structure identification of hetisine type alkaloids from aconitum coreanum, evaluation its antiarrhythmic activities, and explore the mechanism of selective blocking of Na+ or K+ channels and structure-activity relationship of hetisine type alkaloids. It is provided the scientific basis on research and development of safe and effective antiarrhythmic drugs.