Diabetics display evidence of abnormalities in vascular function before changes in vascular anatomy occur. In order to learn more about the mechanisms responsible for the aberrations in function, we propose to study the major control mechanisms of the blood vessels of the brain, heart, muscle and skin of dogs with alloxan-induced diabetes mellitus. We will also study the coronary collateral flow development. These dogs will have the metabolic and hormonal abnormalities of diabetes but not the microangiopathy which develops later. We will observe the effect of (a) severity of the diabetes, and (b) control of the plasma glucose concentration on vascular control mechanisms. Our purpose will be to uncover differences between control and diabetic dogs with respect to reflex, neural, humoral and local control. To this end we will also investigate the response of isolated blood vessel strips from each of the above organs. We will use radioactive microspheres to determine each of the four organ blood flows during hemorrhage and exercise in awake dogs. Awake dogs will also be used to assess the effects of diabetes on the development of coronary collateral blood flow. Various organ blood flow techniques will be used for further studies of resistance and capacitance vessels (muscle and skin) in anesthetized dogs. These experiments will include stimulation of sympathetic nerves, intra-arterial infusion or norepinephrine, isoproterenol and angiotensin, cardiac pacing, exercise, exposure of skin to low and high temperatures, alterations in arterial pCO2 and reactive hyperemia. Specific hypotheses to be tested include: (a) increased vasoconstrictor responsiveness of resistance vessels of diabetics to norepinephrine because of beta receptor mediated vasoconstriction, (b) poor metabolic regulation of flow of diabetics because of altered potassium release, osmolarity, pCO2, etc., (c) exaggerated cutaneous vasoconstrictor response of diabetic skin to cold, (d) diminished coronary collateral growth in diabetics because of insulin lack.