The long-term objectives of this research plan are to determine how the vascular smooth muscle cell and mechanical characteristics of microvessels adapt to various pathological and physiological stresses, and to identify the regulatory mechanisms responsible for these adaptations. Physical work and exercise are constant physiological stresses, and exercise training is often prescribed in the treatment and management of various pathological conditions such as hypertension, diabetes, and obesity. The focus of the current proposal is to investigate the mechanisms responsible for the changes in vascular smooth muscle function and regulation of peripheral vascular resistance which result from aerobic exercise training in normotensive and hypertensive animals. Specifically, the goals of this proposal are to determine 1) if the vascular reactivity of skeletal muscle arterioles to various vasodilator and vasoconstrictor stimuli is altered as a result of exercise training, 2) if the enhanced functional hyperemia which is known to occur in trained skeletal muscle results in an excess delivery of oxygen to the contracting skeletal muscle tissue, 3) if arteriolar reactivity to constrictor stimuli is altered in a non-muscle tissue, the small intestine, as a result of aerobic training, 4) if the changes in vascular function resulting from training are similar between normotensive and hypertensive animals, and 5) if anatomical or mechanical changes contribute to a decline in peripheral vascular resistance in trained skeletal muscle of hypertensive animals. Arteriolar properties will be evaluated in the spinotrapezius muscle and small intestine of sedentary and aerobically trained normotensive Wistar-Kyoto and Spontaneously Hypertensive rats. Vascular reactivity will be assessed by measurement of arteriolar diameter and pressure during superfusion of adenosine and norepinephrine, application of a myogenic stimulus using the """"""""box"""""""" technique, arterial hypoxia induced by respiration of a nitrogen-room air mixture, and stimulation of endothelial derived relaxant factor release by local application of acetylcholine. Arteriolar and venular hemoglobin oxygen saturation and the relative change in tissue NADH concentration will be evaluated in the resting and contracting muscle using image analysis techniques to evaluate the relative relationship of oxygen delivery to metabolic demand. Microvascular blood flow will be determined by measuring labeled red cell flux. Functional arteriolar and capillary density will be measured in the resting and contracting muscle and anatomical vessel density will be measured in fixed tissues. The passive mechanical characteristics of the arteriole wall will be evaluated in vivo and will be used to determine the active and passive contributions to total wall tension during the various perturbations. Total wall and vascular smooth muscle cross-sectional areas will be determined in fixed tissues and used to calculate changes in total and active wall stress during in vivo perturbations. The results of this study will elucidate the mechanisms responsible for the decline in peripheral vascular resistance known to result from aerobic exercise training in both normotensive and hypertensive animals, and may provide insight to the inherent physiological efficacy of exercise training in the treatment and prevention of various diseases which involve microvascular pathologies.
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