Many of the mechanisms which are responsible for changes in cardiac output and peripheral vascular resistance during exercise and the role of these mechanisms after chronic exercise training, have been elucidated. However, it has recently been recognized that increases in blood flow velocity, perhaps through changes in shear rate (or stress), in and of itself, result in vasodilation of both large arteries and resistance vessels through an endothelial cell-EDRF dependent mechanism. Since exercise is a state characterized by large increases in blood flow in the coronary and skeletal muscle circulations, the investigators have hypothesized that acute exercise stimulates EDRF dependent dilation of large and small blood vessels and furthermore that chronic exercise conditioning, ie. aerobic training, potentiates the release of EDRF even further.This enhanced release is most likely due to the increased production of EDRF by the constitutive enzyme and may be responsible for the beneficial cardiovascular effects of exercise in human disease states. The investigators preliminary data suggest that the increase in large coronary artery diameter in vivo during exercise is eliminated by nitro-L-arginine, an inhibitor of arginine metabolism. The increase in systemic arterial pressure during exercise is even larger after blockade of EDRF synthesis. Chronic exercise conditioning (2 hours at 7 miles per hour for 10 days) enhances the large coronary artery dilation to acetylcholine in conscious dogs through an EDRF dependent mechanism. In vitro, large epicardial and isolated coronary microvessels from the dogs after chronic exercise have an increased release of nitrite, the hydration product of NO, in the basal state and also after stimulation with acetylcholine. Northern blot analysis of freshly harvested aortic endothelial cells from these dogs indicates the presence of constitutive EDRF synthase. The focus of the investigators' studies will be to determine: 1) the role of EDRF in the acute cardiovascular response to exercise; 2) the role of EDRF after chronic exercise conditioning; 3) if NO is the mediator of these effects; and, 4) whether there is enhanced production of the mRNA for EDRF synthase after chronic exercise conditioning. Chronic exercise conditioning not only increases blood flow to the organs which participate in the exercise response but also reduces systemic hypertension, may partially reverse the effects of heart disease and may promote general cardiovascular well being.The investigators' preliminary data suggest that EDRF directly participates in this exercise conditioning, and the investigators' study will define in vivo the role of EDRF and will determine in vitro the biochemical and molecular mechanisms responsible.
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