This is a competitive renewal application to study the role of nitric oxide on cardiovascular regulation in response to exercise. During the previous period of funding the applicant and his collaborators established that exercise training increases endothelial nitric oxide synthase gene expression. They also found evidence to suggest that nitric oxide may regulate mitochondrial metabolism and oxygen uptake and substrate utilization by the heart during exercise. The studies that are proposed in this application build logically on these previous observations and will determine the role of nitric oxide in the control of the coronary circulation, oxygen and substrate utilization during moderate to prolonged exercise training. In addition the applicant will study the Greyhound, a breed of dog that has been inbred so as to enhance exercise performance. The hypothesis under question in this analysis will be that this breed of dog has the genetic predisposition both to make nitric oxide and also to increase expression so as to enhance blood flow and oxygen and substrate utilization by the myocardium in response to exercise training. In the third specific aim the applicant will use the ecNOS knock out mouse model to determine whether there are alterations in total body oxygen consumption at rest and during exercise if this enzyme is genetically deleted. Finally the investigators will determine whether the up regulation of nitric oxide production and the control of cardiac metabolism is associated with increased gene expression of ecNOS in coronary vessels from mongrel dogs, Greyhounds and mice. The studies comprise an integrated approach to the study of nitric oxide and its contribution to the regulation of coronary circulation and cardiac metabolism during exercise.
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