迷走神经功能调节与心肌缺血保护

心血管系统的生理活动受自主神经系统(autonomic nervous system,ANS)调节.已有研究表明,自主神经功能紊乱,尤其是迷走神经功能低下,与心血管疾病(cardiovascular disease,CVD)的发生、发展及预后密切相关.本文结合国内外研究现状,就本研究室在迷走神经对心脏不同部位的调控及其对心肌的保护作用机制方面的研究成果进行阐述.通过收缩功能检测及标准玻璃微电极细胞内记录技术,发现迷走神经递质--乙酰胆碱对哺乳动物心室肌有直接作用,可抑制细胞收缩力及动作电位时程;通过组织化学染色及分子生物学方法进一步证明心室有毒蕈碱受体分布;通过膜片钳技术显示在部分动物心室肌上存在乙酰胆碱激活的内向整流钾通道(acetylcholine-activated potassium channel,KACh),并且其电流(IK·ACh)和心房肌一样具有衰减现象.前期研究证明心房肌IK·ACh的衰减与毒蕈碱受体、G蛋白或钾通道磷酸化有关;而心室肌的IK·ACh还有待于进一步研究.我们建立了相关动物模型,结合心率变异性分析等自主神经评价方法,探讨ANS在健康和疾病状态下的变化情况,证明了迷走神经对心脏调节的增龄性改变及代偿效应.通过提高迷走张力(乙酰胆碱缺血预/后适应、有氧运动、β受体阻断剂),研究改善自主神经平衡对缺血心肌的保护作用以及胆碱能抗炎通路防御缺血,再灌注诱导的炎症损伤机制.综合评价心脏自主神经调节,改善交感和迷走张力平衡,将为CVD防治的基础研究提供重要的理论依据.

Vagal control of cardiac functions and vagal protection of ischemic myocardium

The physiological activities of the cardiovascular system are under the control of autonomic nervous system (ANS). Recent researches have found that autonomic dysfunction, especially the withdrawal of vagal activity, was closely related to the etiology, course and prognosis of cardiovascular disease (CVD). Based on the current status and our achievements in this area, we discuss vagal regulation of different parts of the heart and the mechanism of vagal protection of myocardium. Using a force transducer and standard microelectrodes recording technology, we found that the vagus nerve transmitter--acetylcholine (ACh) had direct effects on ventricular myocytes in mammals: It inhibited the contractility and shortened the action potential duration of cardiac myocytes. We proved the existence of muscarinic receptors and vagal nerves innervation in ventricle with histochemical staining and molecular biological methods. Furthermore, ACh-activated potassium channel (KACh) was found in the ventricles of some animals by patch-clamp. Fade of the current (IK.ACh) to ACh in atrium was found in previous research, which was related to the muscarinic receptors and phosphorylation of G protein or potassium channel. However, the mechanism of the fade in ventricle needs to be further investigated. Combined with autonomic nervous evaluation methods (heart rate variability analysis) and relevant animal models, we studied the regulation of ANS during normal and morbid state, and proved the age-associated changes and compensatory effects of vagal control of hemodynamics after unilateral vagotomy. By increasing the vagal tension (ACh induced-preconditioning/postconditioning, aerobic exercise, beta receptor antagonist), we demonstrated protective effects of the vagus nerve on the ischemic myocardium and mechanism of the cholinergic anti-inflammatory effects on the inflammatory reaction induced by reperfusion injury. Evaluating cardiac autonomic nervous regulation and improving balance between sympathetic and vagal nerve will provide an important basis for the prevention and treatment of CVD.