Substantial Production of Dopamine in the Human Gastrointestinal Tract

Abstract

Considerable urinary excretion of dopamine metabolites indicates that large amounts of dopamine are produced in unknown locations of the body. This study assessed the contribution of mesenteric organs (gastrointestinal tract, spleen, and pancreas) to the total body production of dopamine in humans and examined the presence of the rate-limiting enzyme for dopamine synthesis, tyrosine hydroxylase, in gastrointestinal tissues. Blood sampled from an artery and portal and hepatic veins in eight subjects and from arterial and renal venous sites in other subjects was analyzed for plasma concentrations of dopamine and its metabolites. The activity and distribution of ty-rosine hydroxylase was also examined in tissue samples from the stomach and duodenum. Higher concentrations of dopamine and its metabolites in portal venous than arterial plasma indicated substantial production of dopamine by mesenteric organs (12.0 nmol/min) amounting to 42-46% of the renal removal of circulating dopamine metabolites. Tissue samples showed immunoreactive tyrosine hy-droxylase in nonneuronal cell bodies and detectable levels of tyrosine hydroxylase enzyme activity. The results show that mesenteric organs produce close to half of the dopamine formed in the body, most of which is unlikely to be derived from sympathetic nerves but may reflect production in a novel nonneuronal dopaminergic system. (J Clin Endocrinol Metab 82: 3864-3871, 1997) D OPAMINE (DA) in the gastrointestinal tract stimulates exocrine secretions, inhibits gut motility, modulates sodium absorption and mucosal blood flow, and is protective against gastroduodenal ulcer disease (1-5). Thus, DA is more than a metabolic intermediate in the formation of norepi-nephrine (NE) and epinephrine and has distinct biological actions of its own. This concept is supported by the presence of DA receptors throughout the gastrointestinal tract (6-10). However, a source of the DA agonist for these receptors, other than from sympathetic nerves, has not been identified. The existence of a peripheral DA system, independent of the sympathoadrenal system, is suggested by the considerable DA formed in the body and not converted to other catecholamines (11). Although originally thought to reflect DA formation in the central nervous system, it is now clear that the brain is a minor source of DA metabolites (12). The origins of the large amounts of DA produced elsewhere in the body are not established, but could reflect formation within a putative dopaminergic system in the digestive tract. The present study examined how much of the DA produced in the body, and not converted to NE, is derived from mesenteric organs (i.e. the gastrointestinal tract, spleen, and pancreas). For this, net rates of production of the DA precursor , dihydroxyphenylalanine (DOPA), and of DA and its metabolites by mesenteric organs in patients undergoing elective gastrectomy were compared with rates of renal elimination of DA and its metabolites in other subjects studied during cardiac catheterization. Comparisons with other data (13, 14) established the proportions of DA produced at different sites that were converted to NE or catabolized to inactive metabolites. Additionally, the study assessed whether tyrosine hydroxylase, the enzyme responsible for synthesis of DOPA and rate-limiting for subsequent production of catecholamines, is located at sites in the digestive tract other than sympathetic nerve endings. For this, the stomach and duodenum were analyzed for the presence, distribution, and activity of tyrosine hydroxylase by immunohistochem-istry and enzyme assay. The aim of the study was to further define the existence of a putative DA system within mesen-teric organs by establishing the peripheral sources of DA and the presence of tyrosine hydroxylase outside of sympathetic nerve endings in tissues of the digestive tract. Materials and Methods Experimental subjects Blood samples were obtained from 8 patients undergoing elective upper abdominal surgery and 47 subjects undergoing cardiac catheter-ization. Tissue samples were obtained from the wall of the stomach and duodenum in another 5 subjects. Patients undergoing abdominal surgery included 3 females and 5 males (age 47-77 yr, mean 64 yr). A gastric adenocarcinoma provided the reason for surgery in 7 subjects, and a pancreatic neoplasm was the reason for surgery in the other patient. No signs of hepatic or distant metastases were found in any of the patients. Subjects undergoing cardiac catheterization included 11 normal volunteers (all males; age 26-50 yr, mean 36 yr) and 36 patients with con-gestive heart failure (7 females, 29 males; age 35-75 yr, mean 54 yr). Most heart failure patients were in New York Heart Association functional class III (n 30), the rest were in class II. Medications were withheld and