Effect of Daily Exercise on Cardiac Autonomic Regulation

描述（由申请人提供）：流行病学数据表明，有氧运动训练可以显著降低心脏死亡率，即使是已经患有心脏病的患者。这种保护心脏的机制在很大程度上仍有待确定。运动引起的心脏自主调节的改变可能在心脏死亡率的提高中起主要作用。心脏自主神经平衡可因心脏病而改变，改变最大的患者（即副交感神经活动减少和/或交感神经活动增加）也有可能因心室颤动（VF）而猝死的最大风险。运动训练可以增加副交感神经活动，减少交感神经活动，从而降低死亡率。因此，拟议的研究将验证运动训练增强副交感神经和/或减少心脏交感神经活动，从而预防VF的中心假设。具体目标#1将测试运动训练改变易患和抵抗VF的动物心脏自主神经平衡的假设。具体来说，在运动调节计划（每天跑步8-10周）完成之前、期间和之后，将评估对VF有抵抗力或易感的动物的心脏自主神经平衡。对两种不同的生理应激源，亚极限运动和急性心肌缺血的自主神经反应，将进行评估。心脏自主神经平衡将通过药理学试验（激动剂剂量反应、选择性拮抗剂的作用）、压力反射敏感性和R-R间期变异性的时间序列分析来评估。具体目标#2将验证运动训练引起的心脏自主神经变化是这种干预措施的保护作用的假设。副交感神经活动的影响将用胆碱能拮抗剂评估。因此，如果副交感神经增强起保护作用，那么阿托品应该恢复易感动物的VF。具体目标#3将测试运动训练可以逆转β -肾上腺素受体反应性增加的假设，我们已经证明这种反应发生在心肌梗死后易患VF的狗身上。心室对β 1-和β 2肾上腺素能受体刺激的收缩反应将在体内通过超声心动图和体外通过单细胞荧光显微镜/视频边缘检测进行检查。

DESCRIPTION (provided by applicant): Epidemiological data demonstrate that aerobic exercise training can dramatically reduce cardiac mortality even in patients with pre-existing cardiac disease. The mechanisms responsible for this cardio protection remain largely to be determined. It is probable that exercise-induced changes in cardiac autonomic regulation play a major role in the improved cardiac mortality. Cardiac autonomic balance is altered by cardiac disease and the patients with the greatest changes (i.e., decreased parasympathetic and/or increased sympathetic activity) are also at the greatest risk for sudden death presumably due to ventricular fibrillation (VF). Exercise training can increase parasympathetic and decrease sympathetic activity and could thereby reduce mortality. Therefore, the proposed studies will test the central hypothesis that exercise training augments parasympathetic and/or reduces cardiac sympathetic activity and thereby protects against VF. Specific Aim #1 will test the hypothesis that exercise training alters cardiac autonomic balance in animals susceptible and resistant to VF. Specifically, cardiac autonomic balance will be evaluated in animals either resistant or susceptible to VF before, during and after the completion of an exercise conditioning program (8-10 weeks of daily treadmill running). The autonomic response to two different physiological stressors, submaximal exercise and acute myocardial ischemia, will be evaluated. Cardiac autonomic balance will be evaluated by pharmacological tests (agonist dose response, effects of selective antagonists), baroreflex sensitivity, and time series analysis of R-R interval variability. Specific Aim #2 will test the hypothesis that the cardiac autonomic changes induced by exercise training are responsible for the protection noted for this intervention. The effects of parasympathetic activity will be evaluated with a cholinergic antagonist. Thus, if parasympathetic enhancement is responsible for the protection, then atropine should reinstate VF in the susceptible animals. Specific Aim #3 will test the hypothesis that exercise training can reverse the increased Beta-adrenoceptor responsiveness that we have shown to occur in dogs that become susceptible to VF following myocardial infarction. Ventricular contractile responses to Beta1- and Beta2-adrenoceptor stimulation will be examined in vivo by echocardiography and in vitro by single cell fluorescence microscopy/video edge detection.