SYMPATHOADRENAL AND CATECHOLAMINERGIC FUNCTION IN HEALTH AND DISEASE

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Catecholamines are important in normal physiology, stress, and disease. The adrenomedullary hormonal and sympathetic neural components of the sympathoadrenal system use the catecholamines, epinephrine (EPI) and norepinephrine (NE) as the main effector biochemicals. The catecholamines dopamine (DA) and NE are important central neurotransmitters. In the kidney, DA participates in sodium balance. Our goals have been to: (1) understand how the sympathoadrenal system is regulated and its function coordinated with that of other systems; (2) determine the role of brain NE in the expression of neuroendocrine stress responses; and (3) identify bases for abnormal renal Dopa-DA function in disorders of sodium homeostasis such as salt-sensitive hypertension. Positron emission tomography (PET) scanning after systemic administration of [18F]-6-fluorodopamine ([18F]-6F-DA) provided the first noninvasive, in vivo means to examine cardiac sympathetic innervation and function in humans. A multielectrode array electrochemical detector (neurochemical analyzer) was used to assay plasma and urine levels of [18F]-6-DA in humans, and the neurochemical results indicated that [18F]-6-DA is taken up into sympathetic nerve endings and converted to the fluorinated analog of NE. Combined direct sympathetic nerve recording and measurement of regional NE spillover was used to demonstrate that systemic administration of the alpha2-adrenoceptor antagonist, yohimbine, increases NE release by both stimulating sympathoneural outflow and blocking presynaptic alpha2-receptors in humans. in a distinct subgroup of patients with essential hypertension, sympathoadrenal hyperreactivity was indicated by yohimbine challenge testing. In vivo microdialysis in rats showed that yohimbine releases NE into the arterial plasma and into brain extracellular fluid, and that hypercortisolemia abolishes yohimbine-induced release of NE in the brain and periphery. Further evidence for a relationship between endogenous plasma Dopa and catecholamine biosynthesis was obtained in rats, and abnormally increased urinary excretion of Dopa and a low urinary DA: Dopa ratio were found in patients with saltsensitive hypertension. PET scanning, neurochemical analysis, microdialysis, direct sympathetic nerve recording, and molecular biological techniques will be used to elucidate the roles of catecholaminergic systems in health, stress, and disease.