One of the hallmark peripheral adjustments in the state of chronic heart failure (CHF) is activation of a variety of neuro-humoral systems, including the sympathetic nervous system, the renin-angiotensin system and the vasopressin system. Initially, these alterations are of benefit to the organism, helping to maintain perfusion pressure to provide adequate coronary and cerebral blood flow. However, chronically these adjustments become counter productive and contribute to the downward spiral of cardiovascular deterioration characteristic of severe CHF. Understanding the mechanisms by which neuro-humoral activation occurs is crucial to the development of rational strategies for the treatment of patients with CHF. We propose a new program project to investigate the mechanisms by which cardiovascular reflex function is altered in the setting of CHF. We have assembled a experienced group of investigators whose expertise revolved around the reflex control of the circulation. In project I, Drs. Zucker and Patel will investigate the role of central angiotensin II (Ang II) and nitric oxide (NO) in modulating sympathetic outflow in rabbits with experimental CHF. The ameliorating effects of repetitive exercises on reflex abnormalities will also be examined. In project II, Drs. Patel and Pucker will examine the role of NO and the GABAnergic system in the paraventricular nucleus on the modulation of sympathetic outflow in rats with CHF. Project III will be led by Drs. Schultz, Rozanski and Wang. This project is focused on the peripheral chemoreflex and its contribution to augmented sympathetic tone in rabbits with CHF. The involvement of alterations in chemoreceptor NO on the afferent component of the chemoreflex will be investigated. Enhanced chemoreflex sensitivity may contribute to sympatho-excitation in CHF. In project IV, Drs. Wang, Pucker and Schultz will investigate the role of the cardiac """"""""sympathetic afferent"""""""" reflex in the modulation of sympathetic outflow in a canine model of CHF. This excitatory reflex exhibits enhanced sensitivity in CHF and may be mediated by alterations in central AII and NO. Finally, in Project V, Drs. Sinoway and Leunberger will examine the muscle metaboreflex in humans with CHF. They will determine the afferent signal from exercising muscle which is responsible for augmentation of this reflex and the role of exercise on this signal. Microdialysis will be used in patients with CHF to determine the interstitial concentrations of various substances which may be responsible for activating Type III and Type IV afferents. Thus projects, I, II and IV will be concerned with central abnormalities in CHF. Projects III, IV and V will be concerned with afferent abnormalities. All projects unique interrelate to the central theme of neuro-circulatory control in CHF.
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