Previous objectives of this project have revealed several aspects of carotid body (CB) chemoreflex function that are altered in heart failure (HF) and contribute to sympathetic dysregulation. The purpose of this proposal is to elucidate the mechanisms that cause enhanced CB chemoreceptor activity in HF. Using pacing-induced HF rabbits, we will determine whether reactive oxygen species (ROS) contribute to enhanced CB function in HF by reducing bioavailable NO and/or suppressing NOS expression and activity in the CB. We will also explore the notion that Ang II serves as a major source of enhanced ROS in the CB in HF by stimulating NAD(P)H oxidase, and that exercise can serve as an effective therapeutic agent in HF to restore normal CB function by reducing circulating Ang II and its effects on ROS/NO interactions in the CB. We will use the conscious animal, organ (CB nerve recording), cellular (patch clamp, histochemical), pharmacology, and biochemical/genomic/molecular techniques to test these Aims. We will determine which K+ (KV, KCa++, HERG-like/TASK) and Ca++ (L, N, P/Q) channelsubtypes are altered in CB glomus cells in HF; whether the NO system contributes to the HF-induced changes in these ion channel functions, and whether NO effects are mediated by cGMP; We will determine whether ROS contribute to the HF-induced changes in ion channel function(s) observed in glomus cells, and if so, whether they act by reducing NOS/NO. We will determine whether Ang II contributes to altered ion channel function(s) observed in glomus cells, and whether these effects are mediated by NAD(P)H oxidase and ROS production. We will assess functional correlates of effects observed in glomus cells by determining effects of similar pharmacological and genomic manipulations on CB afferent discharge and reflex function. We will determine whether exercise training normalizes glomus cell ion channel function and CB afferent sensitivity in HF, and whether this effect is mediated by a reduction in Ang II, NAD(P)H oxidase, and ROS, and elevation of NOS/NO. And, we will assess the contribution of the CB to reduced sympathetic outflow and plasma norepinephrine with exercise training in HF by selective denervation of the carotid body. These studies will provide new information about the interaction of Ang II, ROS, and NO on neuronal excitability in the CB in the HF state and provide new insights into the beneficial effect of exercise on autonomic function in HF, via effects on CB afferent function. This proposal allies the theme of other projects of this PPG and will fully utilize all corefacilities. Our unique emphasis on ion channel function will provide useful insights for collaborations with the other projects of the PPG.
Showing the most recent 10 out of 169 publications