The effects of histamine, Nalpha-dimethylhistamine, 4,5-methylhistamine, Ntau-methylhistamine, pentagastrin, carbachol, and NaF on the adenylate cyclase activity from canine gastric mucosa were investigated in cell-free preparations. In gastric fundic mucosa, histamine (10(-4) M), Nalpha-dimethylhistamine (10(-4) M), 4,5-methylhistamine (10(-4 M), and NaF (10)-2) M) significantly (P less than 0.001) increased adenylate cyclase activity (means+/-SE) by 44.7+/-6.6, 49.4+/-6.7, 34.0+/-6.4, and 572.0+/-100%, respectively, above basal activity. The effect of histamine and Na-dimethyl histamine was dose-dependent. In contrast, other tested agents failed to stimulate the formation of cyclic AMP in gastric fundic mucosa. Metiamide (10(-4) M) blocked the stimulation of fundic mucosa adenylate cyclase by histamine and Nalpha-dimethylhistamine, without significantly altering basal and NaF-induced adenylate cyclase activity. Histamine, however, did not stimulate the adenylate cyclase activity from the gastric antral mucosa. The findings support the proposal that the canine gastric acid response to histamine may be mediated by cyclic AMP formed in response to stimulation of histamine H2-receptors.