This project centers on examination of how the sympathetic nervous system and other catecholaminergic systems function to integrate and regulate physiological processes at subcellular, cellular, and multi-organ levels in health and disease. Studies of patients with chromosomal deletions affecting monoamine oxidase, an enzyme responsible for metabolism of catecholamines, revealed three separate genetic defects affecting the enzyme. The three disorders are associated with distinct neurochemical, behavioral, & neurological phenotypes. The findings provide insight into how the enzyme functions in catecholamine metabolism, as well as how abnormalities of the enzyme may lead to developmental abnormalities in the expression of behavior. Measurement of plasma free (unconjugated) metanephrines, O-methylated metabolites of catecholamines, in patients with pheochromocytoma indicated that these metabolites provide a considerably more sensitive marker of the tumor than conventional measurements of plasma catecholamines or urinary metanephrines. Findings that large amounts of metanephrines are produced within the adrenals provide an explanation for the extraordinary sensitivity of plasma levels of these metabolites for diagnosis of pheochromocytoma; even when not actively secreting catecholamines the tumors are actively metabolizing catecholamines to metanephrines. Studies of cardiac sympathetic function in congestive heart failure indicated that increased sympathetic drive to the failing heart is secondary to both an increase in neuronal release of transmitter and a decrease in the efficiency of transmitter reuptake. Examination of patients at various stages of heart failure revealed that the changes in cardiac sympathetic function precede changes elsewhere in the body. Studies of how the handling of catecholamines is integrated among different organs and tissues of the body indicate that the liver removes most of the norepinephrine and its metabolites that are released by upstream mesenteric organs. This revealed that a previously unrecognized major proportion of sympathetic outflow is directed to mesenteric organs. Substantial dopamine production by mesenteric organs also suggests the presence of a novel dopaminergic autocrine/paracrine system within the gastrointestinal tract. The system may be involved in bicarbonate secretion and absorption of sodium, functions that may be relevant to several disorders such as salt-sensitive hypertension, idiopathic edema, and ulcer formation.
