Molecular and Cellular Determinants of the Exercise Pressor Reflex in CHF

DESCRIPTION (provided by applicant): Chronic heart failure (CHF) is one of the leading causes of death in the U.S. A hallmark of CHF patients is elevated sympatho-excitation and exercise intolerance during physical activity. Even during moderate exercise, extreme activation of the sympathetic nervous system is often seen causing an exaggerated pressor response and hyperventilation, which potentially increases cardiovascular risk during physical activity in these
patients. Existing evidence indicates that the exaggerated sympatho-excitation during exercise is directly related to increased contribution of the exercise pressor reflex (EPR). However, the molecular and cellular mechanisms underlying the increased EPR in CHF remain to be determined. Due to underperfused areas of skeletal muscle in CHF, release of reactive oxygen species and inflammation may activate the mitogen-activated protein kinase (MAPK) pathways in muscle afferent neurons. We hypothesize that chronic oxidative stress in muscle afferent terminals initiate activation of the MAPK signaling pathway in muscle afferent neurons in CHF. This activation, in turn, increases the afferent input of the EPR by affecting afferent neuronal excitability. At the cellular level, we hypothesize that enhanced voltage-gated sodium channel (Nav) activity in muscle afferent neurons (DRG's) of CHF rats contributes to the enhanced afferent neuronal excitability and the EPR. Since exercise training (ExT) prevents the exaggerated EPR in a myocardial infarction rat model we propose that ExT prevents the exaggerated EPR, in part, by inhibition of excessive activation of the MAPK pathway. We will use highly integrative techniques including molecular (real-time PCR, single cell real-time PCR, western blot, immunofluorescence, and in vivo gene transfer), cellular (patch clamp) and whole animal experiments (measuring EPR function, single afferent recording) to test these hypotheses. We believe that the proposed research will address important functional and mechanistic issues that directly relate to the quality of life in patients with CHF. Furthermore, w believe that these data will uncover new targets for therapy in CHF.