The principal objective of the proposed study is to examine aspects of sympathoadrenal function and catecholamine inactivation in animal models of diabetes with specific emphasis on the vasculature. Rats and rabbits will be rendered diabetic by treatment with a diabetogenic agent. Selected blood vessels will be removed from diabetic and age matched control rats and the following neuroeffector processes examined: (1) release of neuronal norepinephrine (NE) and dopamine hydroxylase (DBH) with stimulation of sympathetic nerves in the rat; (2) the inactivation of catecholamines by neuronal and extraneuronal metabolism; (3) pharmacological responses to electrical stimulation in the absence and presence of agents known to block neuronal and/or extraneuronal uptake; and (4) the activities of the NE synthesizing enzymes in vascular tissue. In all of the preceeding experiments, focus will be directed toward the early (onset) and late (established) stages of diabetes as well as the effects of insulin replacement, thyroid hormone therapy and adrenalectomy. The methodological procedures will include incubation of segments of blood vessels in the presence of tritiated NE, (3H NE) analysis of the tritiated metabolites of 3H NE by paper chromatography and radiochemical assay of the activities of the NE metabolizing enzymes [monoamine oxidase and catechol-O-methy (transferase)] and NE synthesizing enzymes (DBH, and Tyrosine Hydroxylase). Endogenous catecholamine concentrations will also be measured using high pressure liquid chromatography combined with electrochemical detection. A second aspect of the proposed investigation explores the possibility that adrenoceptors may influence the severity of vestigation explores the possibility that adrenoceptors may influence the severity of diabetes produced by administration of a diabetogenic agent. The long-term objectives are two-fold. Firstly, to better understand the functioning of the sympathetic neurons systems in the diabetic state, and secondly, to explore the possibility that changes in function of the sympathetic nerves innervating the vasculature may play a role in the development of the pathological vascular disease states associated with diabetes.
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