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.
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