迷走神经低强度刺激对心房肌钾离子流和PI3K/NO信号通路的影响研究

Vagus nerve stimulation (VNS) in different levelscan slow the heart rate, shorten the atrial effective refractory period (ARP)and promotes atrial fibrillation (AF) by increasing the heterogeneity of atrial refractoriness.Recent studies suggested that low level vagus nerve stimulation (LLVNS), which do not slow the heart rate, is in fact anti-arrhythmic, but the exact mechanism is unclear. Such anti-arrhythmic effects occurred by prolonging the ARP, decreasing the window of vulnerability(WOV) and increasing the induce threshold of AF. ． Nitric oxide(NO) facilitates supra-threshold vagal neurotransmission at the pre-synaptic level within the cardiac autonomic ganglia (ganglionated plexi, GP).The phosphatidylinositol-3 kinase (PI3K) signaling pathway controls various biological processes in the heart. Meanwhile, PI3K /NO signaling pathway can be activated by acetylcholine.. Thus, we designed these series of experiments to explore the mechanism of LLVNS-mediated anti-arrhythmic effects in acute and chronic AF canine model .The role of LL-VNS plays in the change of the acetylcholine sensitive potassium ion channel(IkAch) , the different expression of potassium ion channels protein(Kir 3.1 and Kir 3.4) and the PI3K signaling pathway will be deeply studied on cellular and molecular level,. Moreover, the determination of the mechanism may ultimately not only enrich the theories of induction and maintenance of AF, but also provide a new thought and method for treating AF by potassium ion channel modulators and neuropeptides.

不同强度的迷走神经刺激可以减慢心率，缩短心房有效不应期（ARP），增加其各异向性，促进心房颤动（房颤）发生；而低强度迷走神经刺激（LL-VNS）并不减慢心率，却能延长心房ARP，减小房颤诱发窗口（WOV），提高房颤诱发阈值，表现出抗心律失常作用，但是其机制不明。一氧化氮（NO）可在心脏自主神经节（GP）突触前水平上调迷走效应，磷脂酰肌醇-3-激酶（PI3K）信号通路可以调控多种心脏生理活性，PI3K/NO通路可被心房乙酰胆碱激活。本研究课题制作动物犬急性和慢性房颤模型，从细胞和分子层面深入研究LL-VNS对心房肌细胞乙酰胆碱敏感钾离子通道电位（IkAch）、钾离子通道蛋白（Kir 3.1和Kir 3.4）表达差异以及PI3K/NO信号通路的影响，探讨LL-VNS抗心律失常机制，丰富房颤发生和维持理论，开辟研究新领域，为钾离子通路调节剂和神经调节肽防治房颤提供新的手段和理论依据。

心脏自主神经失平衡在房颤的诱发和维持扮演重要角色。近年来，低强度的迷走神经刺激作为一种自主神经再平衡技术在抗房颤治疗中已得到国内外诸多电生理学者的广泛关注，但目前具体机制尚不清楚。鉴于此，本项目通过建立犬阵发性房颤的模型，探讨（1）肺静脉和心房的电生理特性及其在房颤触发和维持中的作用；（2）房颤模型中肺静脉和心房结构组织中缝隙连接蛋白的表达变化；（3）房颤模型中电重构与结构重构的之间的联系；（4）无创性迷走神经刺激对房颤电学重构和组织学重构的影响。取得如下重要结果：（1）快速心房起搏能诱导肺静脉和心房缝隙连接蛋白表达下降，形成电重构与结构重构的恶性循环；（2）无创性迷走神经能改善由快速心房起搏诱导的有效不应期的降低及房颤易感窗口，减轻心房电重构；（3）无创性迷走神经能延缓房颤模型中缝隙连接蛋白的表达下调。相关文章已被国际知名杂志收录并刊登。本研究进一步深入探讨了房颤发生的机制，为房颤的预防策略制定提供一定的指导意义。