κ-阿片受体信号转导系统介导电针改善心肌顿抑的机制研究

Myocardial stunning (MS), a post-ischemia myocardial malfunction, usually occurs after the attack by either unstable or overwork-induced pectoris angina. It also happens following various interventional cardiac operations. Lasting MS can eventually cause serious heart failure, even death. Thus, seeking for the effective therapies to prevent and treat MS has become a global hot focus. Previous studies showed that acupuncture can improve the myocardial ischemic injury. But it’s difficult for acupuncture to exert its ameliorative effect on the myocardial ischemic damage due to that the patients attached acutely by myocardial ischemia such as coronary heart disease rarely came to see acupuncturist. Comparatively, MS is more operable to be treated by acupuncture as compared with other acutely-attacking myocardial ischemia because of that patients with MS are not acutely attacking and the state of the illness is relatively milder. However, no study has been reported so far on the improvement of MS by acupuncture. Researches on acupuncture analgesia suggested that acupuncture can increase opioids production and activate opioid receptor system. Furthermore, recent studies showed that opioid receptors and their signal transduction pathways are involved in the mediation of the improvement of myocardial ischemic injury through its direct and indirect effects. It’s reasonable that acupuncture may activate opioid receptors and their signaling pathway to ameliorate the MS-induced myocardial ischemic malfunction. The aim of the present study was firstly to confirm the ameliorative effect of acupuncture on myocardial ischemic injury induced by MS in animal model and then to explore how the kappa-opioid receptors and their signal transduction pathways to mediate the effect. The completion of the study is expected to provide the scientific basis on effective amelioration produced by acupuncture on the myocardial malfunction caused by MS and create a new operable way for using acupuncture to treat myocardial ischemic disease in clinic.

心肌顿抑(myocardial stunning，MS)为缺血后心肌功能障碍，常见于不稳定性/劳累性心绞痛发作后及各种心脏介入术后等，严重时可引发心衰甚至死亡。寻找MS的有效防治手段己成全球热点课题。以往研究显示针刺可改善心肌缺血性损害，但因冠心病急性发作时病情凶险，很少来针灸科治疗，针灸很难发挥作用；而缺血或治疗后出现的MS采用针灸治疗却具有较好的临床可操作性，而有关针刺改善MS的工作迄今无人涉足。针刺镇痛的研究表明，针刺可增加体内阿片类物质并激活阿片受体，现代医学研究提示，阿片系统可经直接和间接作用，参与改善心肌缺血性损伤。因此，针刺极有可能通过作用于心脏阿片受体系统而改善MS的心肌功能障碍。本项目拟采用MS动物模型，观察电针对MS的作用，并系统探讨心脏κ型阿片受体及其信号转导路径在介导该针效中的机制。为针刺防治MS提供科学依据，并为针刺治疗心肌缺血性疾病开辟一条操作性强的新途径。

心肌顿抑为缺血后心肌功能障碍，常见于不稳定性/劳累性心绞痛发作后及各种心脏介入术后等，严重时可引发心衰甚至死亡。寻找心肌顿抑的有效防治手段己成为全球热点课题。本研究以短暂心肌缺血/再灌注造成的心肌顿抑动物模型为研究对象，采用分子生物学、小动物B 超、形态学、电生理学、在体血流动力学分析、单个细胞内钙瞬变和单个细胞收缩同步检测等技术方法，探讨电针干预对心肌顿抑的保护作用，并深入阐明κ-阿片受体及受体后信号转导通路在介导电针改善心肌顿抑中的作用，详细分析该信号转导系统中哪一个或哪一些信号成份在介导上述针效中发挥作用。实验结果表明：电针干预可以明显改善心肌顿抑引起的ST段异常抬高，提高左心室射血分数，增强左心室收缩力，并明显改善左心室的做功，对心肌顿抑引发的心肌缺血性损伤具有一定的保护作用；κ-阿片受体特异性阻断剂nor-BNI可以部分阻断电针预处理改善心肌顿抑的保护效应，尤其对再灌60min后各时间点ST段、左心室收缩压、左心室每搏功和左心室射血分数的四项指标抑制效果明显；而且，电针干预可以提高心肌顿抑大鼠心肌组织κ阿片受体蛋白的表达，提示：κ-阿片受体可能参与介导了电针干预改善心肌顿抑引发的缺血性损伤效应；电针干预的具体作用机制一方面可能是通过增加κ-阿片受体含量，继而作用于κ-阿片受体后直接作用的信号转导系统相关站点，即增强Gq、IP3及DAG的表达、抑制PKC的过度激活；另一方面，通过间接抑制β1-肾上腺素受体后信号转导通路相关站点（包括AC、PKA、L-Ca2+通道）的过度兴奋，从而起到抗心肌顿抑的保护作用。上述研究结果将为针刺防治心肌缺血性损害的临床应用提供了切实的科学证据，并为临床上采用针刺治疗心肌缺血性疾病开辟一条操作性强的新途径。