CARDIAC SYMPATHETIC AFFERENT RELEX IN HEART FAILURE

心衰（HF）的特征是交感神经张力升高。引起心衰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，心脏“交感传入”反射在起搏性心衰犬中增强。这种增强发生的机制尚不清楚。传入纤维对缓激肽和辣椒素的敏感性增强。该实验室的初步证据表明，该反射的中央增益增强也是该反射增强的原因。此外，我们已经证明中枢血管紧张素II （Ang II）至少是这种增强的一种介质。心衰患者心脏交感神经传入反射增加的第二个机制可能是调节交感神经流出的几个中心部位一氧化氮（NO）的产生减少。我们假设中枢Ang II的增加和中枢NO的减少都有助于心衰犬心脏交感传入反射和强直性交感-兴奋状态的敏感性增加。因此，该项目的具体目标是：1)确定心衰犬心脏交感传入反射的中枢增益是否与中枢Ang II水平升高或Ang II 1型受体密度变化有关，或两者兼有；2)确定急性和慢性中枢给药Ang II受体拮抗剂、氯沙坦、L-158,809和/或NO供体是否能预防或减少心衰犬心脏交感传入反射的增强。3)确定缓激素、前列腺素和NO是否为心衰犬心脏交感感觉末梢敏感性增强的介质；4)确定慢性胸椎交感神经传递障碍是否改变了起搏性心衰发展过程中交感神经兴奋反应的时间进程和/或强度。这些研究纳入了本项目的总体范围，因为心衰患者交感神经流出的调节可能是由多种外周输入介导的，并由中枢物质进行重要调节。在这种疾病状态下，心脏交感神经对神经体液调节的理解应该包括这种潜在的有效反射。

Heart failure (HF) is characterized by an elevation in sympathetic tone. The mechanisms responsible for the sympatho-excitation of HF are not completely understood. Recent studies from this laboratory have shown that the cardiac "sympathetic afferent" reflex is enhanced in dogs with pacing-induced HF. The mechanisms by which this enhancement occurs are unclear. There is an enhancement in afferent fiber sensitivity to bradykinin and capsaicin. Preliminary evidence from this laboratory suggests that an enhanced central gain of this reflex is, in addition, responsible for the augmentation of this reflex. Furthermore, we have shown that central angiotensin II (Ang II) is at least one mediator for this enhancement. A second mechanism which may explain the increased gain of he cardiac sympathetic afferent reflex in HF is a decrease in nitric oxide (NO) production in several central sites which regulate sympathetic outflow. We hypothesize that both an increase in central Ang II and a decrease in central NO contributes to the increase in the sensitivity of the cardiac sympathetic afferent reflex and to the tonic sympatho-excitatory state in dogs with HF. Therefore, the specific aims of this project are to: 1) determine if the central gain of the cardiac sympathetic afferent reflex in dogs with HF is related to increased levels of central Ang II or to changes in Ang II type1 receptor density or both, 2) determine if acute and chronic central administration of the Ang II receptor antagonist, losartan and L-158,809 and/or NO donors prevent or reduce the enhancement of the cardiac sympathetic afferent reflex in dogs with HF, 3) determine if bradykinin prostaglandins and NO are mediators of the enhanced sensitivity of cardiac sympathetic sensory endings in dogs with HF, and 4) determine if chronic thoracic sympathetic deafferentation alters the time course and/or magnitude of the sympatho-excitatory response during the development of pacing-induced HF. These studies integrate into the overall scope of this Program Project in that the regulation of sympathetic outflow in HF is likely to be mediated by a variety of peripheral inputs with important modulation from central substances. The cardiac sympathetic understanding of neuro-humoral regulation in this disease state should include this potentially potent reflex.