Enhanced cardiac sympathetic afferent reflex in CHF

University Of Nebraska Medical Center, Omaha NE

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Abstract

[unreadable] 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. [unreadable] [unreadable]