In the US, congestive heart failure (HF) is a common and lethal disease with 500,000 patients being diagnosed, and with ~300,000 deaths each year. Sympathoexcitation plays a prominent role in disease progression. It is known that sympathoexcitation is inversely related to disease prognosis. Sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF patients at rest and in response to exercise. These exaggerated SNA responses are well correlated with morbidity and mortality in HF patients. The long-term goals of the PI are to better understand the mechanisms that regulate the autonomic nervous system during exercise in HF. The mechano- and metabo-sensitive muscle afferents contribute to regulation of SNA in HF. The receptors that stimulate those muscle afferents have yet to be precisely identified and characterized. Over the last several years our research efforts have focused on the roles played by purinergic P2X receptors, capsaicin receptors (TRPV1) and acid sensing ion channels in evoking abnormal SNA responses to muscle contraction in HF. The data indicate that abnormalities in those receptors in primary afferent neurons may initiate the development of an exaggerated muscle reflex in HF. While our laboratory and others have collected substantial evidence showing alternations in muscle afferent-mediated response in this disease, little is known regarding the underlying receptor mechanisms of primary afferent neurons. Prostaglandins and adenosine are important by-products in active muscles and engaged in the abnormal reflex response in HF.
Specific Aim #1 of this proposal is to examine contributions of prostaglandin to exaggerated muscle reflex in HF. We hypothesize that prostaglandins facilitate responses of P2X receptors in the dorsal root ganglion (DRG) neurons of HF rats.
Specific Aim #2 of this proposal is to determine contributions of adenosine to blunted muscle metaboreflex in HF. We hypothesize that adenosine inhibits TRPV1 responses of DRG neurons to a greater degree in HF as compared with controls. The proposed experiments are based on recently published work from our laboratory as well as pilot data that have been gathered and will be performed on dissociated DRG cells using whole cell patch-clamp methods. Completion of these studies will provide an evaluation of muscle afferent-mediated circulatory responses in HF patients at the cellular level. These studies will lay the groundwork for future experiments to examine novel therapeutics to treat exercise intolerance in this disease.
Congestive heart failure is a common and lethal disease in the U.S. The proposed studies in this grant are to examine the role of primary muscle afferent neurons in mediating abnormal sympathetic nerve responses in heart failure.
