The long-range goals of this project are to develop an understanding of the roles and mechanisms of action of oxidant and nitric oxide interactions in vascular function in the coronary circulation and to identify alterations that occur in these processes in the heart failure and exercise training models examined in the Program Project. The first objective is to determine mechanisms that control the production and metabolism of superoxide anion (O(2)) and its interaction with endothelium-derived nitric oxide (NO) that are of potential relevance to signalling functions of (1) the normal coronary circulation and (2) alterations in tissues derived from collaborations within the Program Project on heart failure and exercise training. The second objective is to determine how signalling mechanisms involved in the control coronary vascular tone in normal arteries are altered by O(2))-NO interactions and how changes in this interaction in vascular tissue derived from during heart failure and exercise trained animals result in alterations in mechanisms that control force generation. The third objective is to elucidate the mechanism(s) involved in the control of cardiac (and skeletal muscle) tissue respiration by endothelium-derived NO, with a focus on the role of oxidant interactions in normal cardiac muscle and to identify changes in the function of these processes in tissues derived from the heart failure and exercise training models. Studies in this project examining new signalling mechanisms will be conducted in isolated calf coronary arteries, microvessels and cardiac muscle slices. The collaborative studies focused on examining changes in signalling mechanisms will be conducted on: isolated normal and failing dog coronary arteries, microvessels and cardiac and skeletal muscle slices and isolated normal and exercised rat aorta and skeletal muscle slices, and isolated normal and failing human heart muscle. Collaborative studies on changes in the activity, enzyme levels and mRNA of NO synthase and SOD enzymes will also be employed to identify the origins of changes in the failure and exercise training models. The results of these studies should provide valuable information for understanding the role of oxidant and NO interactions in the function of the coronary circulation, and in identifying changes that occur in the role and mechanism of action of these vascular function-related processes in heart failure and exercise training.
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