Effect of Daily Exercise on Cardiac Autonomic Regulation

描述(由申请人提供)：流行病学数据表明，有氧运动训练可以极大地降低心脏死亡率，即使是在既有心脏病的患者中也是如此。这种心脏保护的机制在很大程度上仍有待确定。运动引起的心脏自主神经调节的改变可能是心脏死亡率提高的主要原因。心脏疾病会改变心脏自主神经的平衡，变化最大的患者(即副交感神经减少和/或交感神经活动增加)也是猝死的最大风险，推测是由于室颤(VF)。运动训练可以增加副交感神经，降低交感神经活性，从而降低死亡率。因此，拟议的研究将检验运动训练增强副交感神经和/或降低心脏交感神经活性从而预防室颤的中心假设。具体目标#1将检验运动训练改变易患和抵抗室颤的动物心脏自主神经平衡的假设。具体地说，在完成运动调节计划(每天在跑步机上跑步8-10周)之前、期间和之后，将评估抵抗或易受室颤影响的动物的心脏自主神经平衡。将评估自主神经对两种不同的生理应激因素的反应，次极量运动和急性心肌缺血。心脏自主神经平衡将通过药理学试验(激动剂剂量反应、选择性拮抗剂的效果)、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将检验这样一种假设，即运动训练引起的心脏自主神经变化对这种干预措施的保护作用负责。副交感神经活动的效果将用胆碱能拮抗剂进行评估。因此，如果副交感增强是起保护作用的，那么阿托品应该恢复易感动物的室颤。具体目标#3将测试这样一个假设，即运动训练可以逆转我们已经证明在心肌梗死后易患室颤的狗身上发生的增强的β-肾上腺素能受体反应性。通过超声心动图和单细胞荧光显微镜/视频边缘检测技术，在活体和体外分别检测心肌对β1和β2肾上腺素受体刺激的收缩反应。

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.