The main objectives of this project are to use animal models to develop and apply methods for examination of sympathoadrenal function, the ultimate goal of this being to extend these studies to the clinical arena. Tissue, plasma or urine samples are obtained before and during pharmacologic or physiologic manipulations and analyzed for concentrations of endogenous and exogenous radiolabelled norepinephrine and epinephrine, as well as their metabolites and precursors. increased plasma concentrations of dihydroxyphenylalanine (DOPA) during stimulation of sympathetic nervous outflow in rats and dogs were shown to be due to increased release from sympathetic nerves. Increased release of DOPA matched the increase in the turnover of transmitter stores indicating that changes in DOPA release provide an index of changes in the activity of tyrosine hydroxylase (TH). Intravenous infusion of tritium-labelled catecholamines in the dog indicated that:(l) the lungs are an important organ for the release of norepinephrine and for the removal of circulating catecholamines; (2) removal is by neuronal uptake-like process, and (3) this process is more efficient for removal of norepinephrine than epinephrine. In rabbits, examination of plasma concentrations of the deaminated intraneuronal metabolite of norepinephrine, dihydroxyphenylglycol, indicated that transmitter concentrations at sites of release were 3.4-fold greater than in plasma, and that this gradient was unaffected by sustained changes in sympathetic activity and was largely dependent on the efficiency of neuronal reuptake. A liquid chromatographic method for the determination of plasma concentrations of the O-methylated catecholamine metabolites, normetanephrine and metanephrine, has been developed to examine the extraneuronal uptake and metabolism of catecholamines. Studies to date using this newly developed technique have concentrated on establishing the source and significance of plasma concentrations of metanephrines.
