The principal objectives of this proposal are a) to investigate further the role of adenosine in the regulation of coronary blood flow b) to determine to what extent this nucleoside mediates blood flow control in other vascular beds and c) to define the steps involved in the synthesis and degradation of the adenine nucleotides in different tissues. The relationship between vascular resistance and adenosine release in skeletal muscle and brain will be studied primarily in the intact anesthetized dog whereas in the lung and kidney isolated perfused organs will be used. Measurements of venous effluent and tissue concentrations of adenosine and its degradative products will be made at different levels of oxygen supply to determine whether vasodilation in the case of lung and kidney are mediated by adenosine. Since vascular smooth muscle constitutes the site of action of adenosine, the direct effect of the nucleoside on the contractile state of stimulated strips of vascular smooth muscle from hog carotid arteries will be studied as well as its uptake, release and metabolism by this tissue. The metabolism of adenosine in normal and hypoxic heart will be examined in a simple two compartment system consisting of suspensions of dispersed and/or cultured chick and rat heart cells whereas localization of the enzymes involved in the cardiac metabolism of adenosine will be carried out by cell fractionation and differential centrifugation of rat ventricular tissue. In skeletal muscle, brain, lung and kidney the formation, degradation and uptake of adenosine as well as its phosphorylation to nucleotides will be studied in intact perfused tissue. These experiments shoudl provide a clearer picture of the relative importance of adenosine as a mediator of metabolic vasodilation in key vascular beds as well as an understanding of the relationship of adenosine metabolism to its action on vascular smooth muscle.