The present study was designed to examine the functional linkage between histamine and somatostatin secretion in the fundus of the stomach. In segments of rat fundic mucosa, superfusion with thioperamide (H3 antagonist) increased somatostatin and decreased histamine secretion; superfusion with (R)(-)-alpha-methylhistamine (H3 agonist) had the opposite effect, decreasing somatostatin and increasing histamine secretion. The pattern implied that endogenous histamine, acting via H3 receptors, exerts an inhibitory paracrine influence on somatostatin secretion. Superfusion with somatostatin antibody (1:250) increased histamine secretion, implying that endogenous somatostatin, in turn, exerts an inhibitory paracrine influence on histamine secretion. Somatostatin antibody also abolished the decrease in histamine secretion induced by thioperamide and the increase in histamine secretion induced by (R)(-)-alpha-methylhistamine, implying that changes in histamine secretion induced by activation of H3 receptors reflect changes in somatostatin secretion. Superfusion with the muscarinic agonist methacholine alone and in the presence of either H3 agonist or H3 antagonist confirmed the existence of reciprocal inhibitory pathways linking somatostatin and histamine. We conclude that fundic histamine and somatostatin secretion are linked via reciprocal inhibitory paracrine pathways that serve to amplify the regulatory influence of somatostatin.