The purpose of this grant is to examine the mechanisms that regulate blood flow in the microcirculation with emphasis on local mechanisms. A major part of this study will examine blood flow autoregulation in skeletal muscle. We have recently observed that stimulation of the sympathetic nerves to the muscle causes a remarkable increase in the autoregulatory response; flow increases 20 to 60% when arterial pressure is reduced locally from 120 to 80 or 60 mmHg. To examine this phenomenon further we will reduce blood flow by 30 to 80% through sympathetic nerve stimulation and lower arterial pressure. This will characterize the magnitude of the enhancement with different degrees of vascular tone. Since previous studies at normal vascular tone have shown that autoregulation is oxygen dependent, we will examine the role of oxygen further at several levels of vascular tone by measuring tissue oxygen tension with a microelectrode. We will also elevate ambient oxygen over the muscle to determine whether the superregulation with increased vascular tone is oxygen dependent. Using a new microscope system we will determine whether changes in tissue metabolic state, as assessed by NADH fluorescence, might be partially responsible for the autoregulatory response at normal and elevated vascular tone. We will test the hypothesis that under increased sympathetic tone the autoregulatory mechanism shifts from an oxygen dependent one to a myogenic response. ADditional studies will examine possible underlying mechanisms for oxygen dependence at normal vascular tone and the apparent shift to myogenic control at elevated vascular tone. We will also examine flow-dependent vasodilation in the microcirculation to determine the role of the endothelium in the response and its contribution to arteriolar dilation in skeletal muscle during muscle contraction. We will also examine the possibility that the endothelium is responsible for an apparent flow-dependent vasoconstriction in cat mesenteric arterioles. These studies are intended to provide a better understanding of the integrated response of the microcirculation during changes in systemic arterial pressure, sympathetic outflow and during muscular exercise.