The regulation of sympathetic nerve activity in the chronic heart failure (CHF) state is a complex and critically important issue. Over the past 20 years this laboratory has been investigating mechanisms of abnormal neuro-humoral control of cardiovascular function in animal models of CHF. We have clearly shown that enhanced sympathetic outflow, which is characteristic of the CHF state, is a multi-factorial process involving alterations in both buffer reflexes and in the central modulation of sympathetic outflow. Based on preliminary data and on recent studies published from this laboratory we proposed to investigate the role of two humoral mediators of sympathetic outflow in CHF. Namely, angiotensin II (Ang II) and nitric oxide (NO). In these studies we hypothesize that a down regulation of the neuronal isoform of nitric oxide synthase (nNos) in specific central sites contributes that a down regulation of the neuronal isoform of nitric oxide synthase (nNos) in specific central sites contributes to an increase in sympathetic outflow in rabbits with pacing-induced CHF. Furthermore, we suggest that an increase in central Ang II contributes to this sympatho-excitation.
In specific aim 1 we will determine the interaction of Ang II and NO on the regulation of resting and reflex mediated changes in renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF. These studies will be accomplished by Intracerebroventricular administration of NO donors, antagonists and Ang II receptor antagonists while evoking the arterial baroreflex and the cardiopulmonary reflex.
In specific aim 2 we will evaluate the role of Ang II on nNOS baroreflex in the cardiopulmonary reflex.
In specific aim 2 we will evaluate the role of Ang II on nNOS production in the brain by measuring both nNOS mRNA and protein. In addition, we will determine the effects of chronic treatment with angiotensin receptor antagonists on nNOS expression and protein in rabbits with and without CHF. Additional preliminary evidence suggests that exercise conditioning (EXC) in CHF can not only reverse the sympatho-excitatory state but can up regulate nNOS mRNA and protein in the brain. Therefore, in specific aim 3 we will determine the role of EXC on resting RSNA and on baroreflex and cardiopulmonary reflex control of RSNA as well as determining the effects of EXC on the central expression of nNOS mRNA and protein. These studies will provide important new information on the regulation of sympathetic outflow in CHF and one of the mechanisms by which exercise may be beneficial to patients with this disease.
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