Duodenal mucosal secretion of bicarbonate is one main mechanism in the protection of this epithelium against luminal acid. The duodenal secretagogue vasoactive intestinal polypeptide, at doses not affecting mucosal blood flow, protects against acid-induced morphological changes. Some sigma receptor ligands, which increase the duodenal alkaline secretion, prevent duodenal but not gastric mucosal ulceration. Dopamine D-1 receptor agonists and the peripherally acting catechol-O-methyl-transferase (COMT) inhibitor nitecapone stimulate the bicarbonate secretion in the rat and a similar increase in secretion has been observed in human volunteers. COMT inhibitors decrease tissue degradation of catecholamines, including dopamine. The D-2 agonist bromocriptine, in contrast, decreases the secretion. These results, indicating that the bicarbonate secretion is stimulated via peripheral dopamine D-1 receptors, are supported by the finding that dopamine D-1 (but not D-2) agonists increase the production of cyclic AMP in isolated duodenal enterocytes. The increase in mucosal alkaline secretion may contribute to the previously observed ulceroprotective actions of dopaminergic compounds.