冠脉内预防性应用山莨菪碱对急性心肌梗死再灌注后心肌微循环障碍/缺血再灌注损伤防治效应及机制的系列研究

Preventively intracoronary administration of different dosages of anisodamine conducts adaptive modulation on myocardial no-perfusion microcirculatory disorder (NP-MCD) before reperfusion of AMI for the prevention and therapeutics of myocardial ischemia-reperfusion injury/microcirculatory disorder (IRI-MCD), and the reduction of no-reflow phenomenon after reperfusion of AMI. The effect of anisodamine on the myocardial perfusion state, viable myocardium, ventricular remodeling and performance was evaluated using quantitative myocardial perfusion classification of coronary angiography combined with Myocardial Contrast Echocardiography (MCE), as well as comparison with those of intracoronary administration of adenosine. Generally, the preventive and protective effects, dose-effect relationship, clinical safety and feasibility of preventively intracoronary administration of anisodamine were proved. Based on the model of myocardial IRI in rat, the effect of anisodamine on mitochondrial KATP level and open state was measured and evaluated before and after myocardial reperfusion. The cytobiological and pharmaceutical mechanisms of the modulation and improvement of myocardial microcirculatory perfusion state as well as prevention and therapeutics of myocardial NP-MCD/IRI-MCD with intracoronary administration of anisodamine were explored.It would be that create a new conception of "modulating the microcirculation firstly, then opening the occluded vessels" and support a chinese special medicine for AMI therapeutics.

冠脉内预防性应用不同剂量山莨菪碱对AMI再灌注前心肌失灌注性微循环障碍（NP-MCD）进行适应性调控，以防治AMI再灌注后心肌缺血-再灌注损伤性微循环障碍（IRI-MCD），减少无复流现象的发生。应用冠脉造影量化心肌灌注分级方法，结合心肌声学显像（MCE）评价山莨菪碱对心肌灌注水平、存活心肌状态、心室重塑与心室功能的影响，并与腺苷进行对照比较，综合论证冠脉内预防性应用山莨菪碱对AMI再灌注后心肌IRI-MCD的预防保护作用和量效关系及其临床应用的安全与可行性；在建立大鼠AMI心肌IRI模型的基础上，测定评价山莨菪碱对心肌再灌注前后线粒体KATP通道开放状态的影响，探讨山莨菪碱预防性给药在调控和改善AMI心肌微循环灌注状态、防治心肌NP-MCD/IRI-MCD中的细胞生物学/药理学机制，为AMI提供"先调微循环，再开通血管"的救治新理念和中国特色药物。

临床部分研究中，继续前期在急性心肌梗死直接经皮冠状动脉介入治疗中冠脉内应用山莨菪碱的相关研究，研究结果发现STEMI-PCI患者支架植入前冠脉内联合应用山莨菪碱和地尔硫卓可明显改善血管造影结果并预防再灌注性心律失常的发生。.在基础研究中，依照标书内容进行了山莨菪碱通过线粒体ATP敏感钾通道预防心肌缺血再灌注损伤的相关研究，结果发现在SD大鼠中使用山莨菪碱后处理具有明显的抗心肌缺血/再灌注损伤作用，表现为显著缩小心肌梗死面积，降低血清CK-MB、LDH含量, 增加心肌ATP含量,保护心肌超微结构。线粒体ATP敏感钾通道阻断剂5-羟基葵酸可显著拮抗山莨菪碱的心脏保护作用，提示山莨菪碱的心肌保护作用与开放线粒体膜ATP敏感钾通道有关。在基础研究部分中，加入了山莨菪碱细胞分子生物学机制方面的相关研究。研究发现山莨菪碱可显著减轻H9c2心肌细胞缺氧/复氧损伤产生的细胞凋亡，其机制可能与山莨菪碱可下调Caspase-3凋亡蛋白及凋亡基因的表达，减少心肌细胞缺血/再灌注损伤相关。.本项目研究成果已发表SCI论文1篇，举办第七届华北长城心脏病学会议、第三届经前臂（桡/尺）动脉微创化冠脉介入治疗国际论坛（2014.11.7-9，河北石家庄），邀请了国际、国内百余名著名心血管病专家进行深入的学术交流，大会参会人数达1500人。同时积极参加国际、国内各地举办的心脏病学术会议（ACC、ESC、TCT、CIT、CCIF、东北心血管病论坛、521会、西部长城会、西京Mayo会、西京复杂冠脉介入会、东方会、南方会等），深入推广冠脉微循环在冠心病PCI治疗中的重要意义及山莨菪碱预处理对冠脉微循环的保护作用。培养3名博士研究生，3名硕士研究生从事冠脉循环相关研究工作。