The long-range goal of the PI is to better understand mechanisms that control blood flow during exercise. The short-range goal of this proposal is to examine the role adenosine triphosphate (ATP) plays in evoking and modulating the pressor response to muscle contraction. The proposed experiments are based on recently published experiments from our laboratory as well as pilot data that have been gathered over the last year. We will evaluate three major aims: 1) we will examine the effects of muscle contraction on ATP release. We hypothesize that interstitial [ATP] rises with contraction. We will also examine whether ischemic and fatiguing contractions raise ATP and stimulate P2X receptors; 2) we will examine the ability of high levels of ATP per se to stimulate and sensitize the muscle reflex response to muscle contraction and stretch. We will raise interstitial ATP using an isolated hindlimb perfusion technique. ATP will be raised to levels seen during contraction. We hypothesize that raising interstitial ATP will evoke a pressor response (in the absence of stretch or contraction) but only at non-physiologic concentrations. We postulate that hindlimb perfusion at physiologic [ATP] will sensitize muscle afferents and increase the pressor response seen with muscle contraction and stretch; 3) We will examine the mechanisms by which ATP is released from skeletal muscle. Pilot data from our laboratory suggests that the skeletal muscle is the source of the increased interstitial ATP seen with contraction. We will examine the role played by skeletal muscle mechanosensitive channels, the role played by cystic fibrosis transmembrane conductance regulator (CFTR) channel, as well as the role played by exocytosis. To accomplish these goals we will employ a decerebrate cat model. In some studies muscle contraction and muscle stretch will be performed as skeletal muscle interstitial ATP is monitored via microdialysis. In other studies an isolated hindlimb perfusion technique will be used to selectively alter interstitial ATP concentration. Finally, we will perform studies in which we use the microdialysis method to deliver compounds in order to determine the mechanisms by which ATP is released from muscle cells. This work will provide new information on the mechanism by which blood pressure is regulated during exercise. This area is important for understanding exercise limitation in a variety of cardiovascular diseases.
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