SYMPATHOADRENAL AND CATECHOLAMINERGIC FUNCTION IN HEALTH AND DISEASE

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Our research has focused on developing and applying methods for assessing the function of central and peripheral catecholaminergic systems and the coordination of these systems with other homeostatic systems in health, stress, and disease. Findings this year include: (1) Positron-emission tomographic (PET) scanning after systemic administration of 6-[18F]fluorodopamine ([18F]-6F-DA) provided a noninvasive, in vivo means to examine cardiac sympathetic innervation and function in humans. This approach can be used to identify clinical disorders of cardiac sympathetic regulation. (2) Clinical microneurographic and allied methods were established to measure skeletal sympathoneural activity directly to diagnose and monitor effects of treatments in a variety of neurocardiologic disorders. (3) An assay method for plasma levels of metanephrines was developed and validated. High normetanephrine levels were noted in all pheochromocytoma patients tested. (4) In healthy humans, dopamine (DA) in urine was found to be derived mainly from renal uptake of plasma DOPA, and low-dose DOPA infusion evoked a marked natriuresis and diuresis. The role of the DOPA-DA system and therapeutic effects of DOPA are being explored in sodium-retaining disorders. (5) Plasma levels of DOPA and dihydroxyphenylacetic acid (DOPAC) reflect in vivo tyrosine hydroxylation, a key aspect of catecholaminergic function. (6) In vivo microdialysis assessments of changes in extracellular fluid concentrations of catecholamines and their metabolites in brain showed: (a) glucocorticoids inhibited the function of alpha2-adrenoceptors on noradrenergic terminals in the paraventricular nucleus; (b) immobilization stress augmented norepinephrine (NE) release in the paraventricular nucleus of the hypothalamus and the central nucleus of the amygdala; (c) juvenile spontaneously hypertensive rats had increased alpha2-adrenoceptor-mediated restraint of catecholamine biosynthesis and NE release in the posterolateral hypothalamus and in the periphery, suggesting a basis for behavioral hyper-activity and hypertension in this rat strain; (d) locally administered glycine produced a net stimulatory effect on striatal DA release; and (e) chronic inhibition of monoamine oxidase A increased exocytotic cerebrocortical NE release. (7) Patterning of neuroendocrine stress responses during acute glucopenia in rats and humans refuted Selye's stress theory.