The overall objective is to determine mechanisms for the altered vascular reactivity observed clinically in diabetes mellitus. The primary hypothesis to be pursued is that altered vascular reactivity in diabetes results from abnormal function of the adrenergic neuroeffector junction and that the diabetic endothelium exerts an abnormal influence on neuroeffector mechanisms and vascular reactivity. Preliminary studies have demonstrated that 1) alloxan-diabetic rabbit carotid arteries have an increased response to in vitro adrenergic nerve stimulation; 2) the increased adrenergic responses is attributable to a decreased inhibitory role of the carotid artery endothelium on adrenergic contractions while responses to endothelium-dependent vasodilators are normal or increased; and 3) a decrease in the content and in vitro electrically stimulated release of endogenous norepinephrine from carotid adrenergic nerves. The proposed in vitro studies will be performed on blood vessels from 6-week alloxan-diabetic rabbits and will determine diabetic alterations in 1) the content, release, reuptake, metabolism, and smooth muscle receptor sensitivity toward norepinephrine released from adrenergic nerves; 2) the influence of the endothelium on responsiveness toward adrenergic stimulation and endothelium- dependent vasodilators as well as the release by these stimuli of PGI2 and non-prostaglandin endothelium-dependent vasodilators; and 3) the response of the blood vessel to the vasoactive substances released from aggregating platelets. The influence of the diabetic melieu itself will be studied by determining the effects of altered glucose and insulin concentrations on normal and diabetic blood vessels. The rationale is that greater understanding of the mechanisms of altered vascular reactivity will result in improved therapy of diabetic patients in whom abnormal vascular reactivity leads to increased morbidity and mortality attributable to an increased incidence of atherosclerosis, microvascular disease, and hypertension.