Enhanced cardiac sympathetic afferent reflex in CHF

描述(由申请人提供)：心力衰竭的特征是交感神经音调升高。心力衰竭中交感神经兴奋的机制尚不完全清楚。该实验室最近的研究表明，心力衰竭时，心脏的“交感传入”反射增强，压力感受性反射减弱。心脏交感传入反射的增强和压力感受器反射的钝化是由心力衰竭时中枢血管紧张素II的增加所介导的。到目前为止，在心力衰竭状态下，这些反射相互作用的机制(S)还不完全清楚。根据初步数据，我们假设心脏交感传入反射的增强是由心力衰竭状态下的中枢血管紧张素II和反应性氧化应激介导的。为了更好地了解心脏交感传入反射增强的机制，我们提出了以下具体目标：1)在心力衰竭中，是否存在通过升高的中枢血管紧张素II介导的活性氧类介导的心脏交感传入反射增强；2)确定心力衰竭动物的心交感传入反射是否钝化压力感受性反射，心外膜应用利多卡因去除心交感传入输入或心外膜应用超强神经毒素白藜芦醇耗竭心交感传入神经递质是否能恢复钝化的压力感受性反射，以及中枢血管紧张素II和自由基是否通过激活心交感传入通路在心力衰竭大鼠钝化的压力感受性反射中起重要作用；3)确定心力衰竭动物的心交感传入反射是否增强化学感受器反射，以及心外膜应用利多卡因或瑞尼费曲辛是否可恢复心力衰竭动物的心交感传入反射，并确定中枢血管紧张素II和自由基是否通过激活心交感传入反射而在化学感受器反射中发挥重要作用；最后4)确定运动训练是否通过减少血管紧张素II和自由基而使心力衰竭大鼠增强的心脏交感传入反射、增强的化学感受器反射和钝化的压力感受器反射恢复正常。这些反射相互作用调节心力衰竭的交感神经流出。心力衰竭状态下异常的交感神经兴奋可能是由多种外周输入所介导的，而中枢物质对其具有重要的调节作用。如果心脏交感传入反射和压力感受器反射是导致心力衰竭时交感神经激活的两种反射，那么全面了解这种反射的神经体液调节可能会导致在这种疾病状态下针对交感神经系统的更明确和合理的治疗。

DESCRIPTION (provided by applicant): Heart failure is characterized by an elevation in sympathetic tone. The mechanisms responsible for the sympatho-excitation in heart failure are not completely understood. Recent studies from this laboratory indicate that the cardiac "sympathetic afferent" reflex is enhanced and the baroreceptor reflex is blunted in heart failure. The augmented cardiac sympathetic afferent reflex and the blunted baroreceptor reflex are mediated by increases in central angiotensin II in heart failure. So far the mechanism(s) responsible for these reflex interactions in the heart failure state are not completely clear. Based on preliminary data we hypothesize that the augmentation of the cardiac sympathetic afferent reflex is mediated by central angiotensin II and reactive oxidant stress in the heart failure state. To better understand the mechanisms responsible for augmentation of the cardiac sympathetic afferent reflex we propose the following specific aims: 1) To determine if reactive oxygen species mediates the augmented cardiac sympathetic afferent reflex by elevated central angiotensin II in heart failure; 2) To determine if the cardiac sympathetic afferent reflex blunts the baroreceptor reflex and if the blunted baroreflex in animals with heart failure is restored by removal of cardiac sympathetic afferent input with epicardial application of lidocaine or depletion of cardiac sympathetic afferent neurotransmitters by the epicardial application of the ultrapotent neurotoxin resiniferatoxin, and to determine if central angiotensin II and free radicals play an important role in the blunted baroreceptor reflex by activation of the cardiac sympathetic afferent pathway in rats with heart failure; 3) To determine if the cardiac sympathetic afferent reflex augments the chemoreceptor reflex and if the enhanced chemoreceptor reflex in animals with heart failure is restored by removal of cardiac sympathetic afferent input with epicardial application of lidocaine or resiniferatoxin and to determine if central angiotensin II and free radicals play an important role in the chemoreceptor reflex by activation of cardiac sympathetic afferents in rats with heart failure; and finally 4) To determine if exercise training normalizes the enhanced cardiac sympathetic afferent reflex, the augmented chemoreceptor reflex, and the blunted baroreceptor reflex in rats with heart failure by decreasing angiotensin II and free radicals. These reflex interactions regulate sympathetic outflow in heart failure. The abnormal sympatho-excitation in the heart failure state is likely to be mediated by a variety of peripheral inputs with important modulation by central substances. If the cardiac sympathetic afferent reflex and baroreceptor reflex are two of the reflexes which contribute to sympathetic activation in heart failure, a comprehensive understanding of neuro-humoral regulation of this reflex may result in more definitive and rational therapy targeted to the sympathetic nervous system in this disease state.