The antisecretory and cytoprotective actions of SCH 28080 (2-methyl-8-(phenylmethoxy)imidazol[ 1,2-a ]pyridine-3-acetonitrile), an antiulcer compound, were characterized. In the isolated guinea-pig gastric mucosa, SCH 28080 at 5 X 10(-8) M abolished the acid secretory responses to histamine and methacholine but at 5 X 10(-7) M also inhibited the responses to dibutyryl cyclic AMP plus theophylline. The data suggest that the antisecretory effect of SCH 28080 involves a direct action on the parietal cells distal to the primary events mediating the cholinergic and H2 histaminergic secretory mechanisms. In the histamine-stimulated dogs, a prolonged suppression of acid secretion was accompanied by only a transient fall in the ratio of mucosal plasma flow to acid output after i.v. dosing of SCH 28080, 1 mg/kg, indicating that the antisecretory action of SCH 28080 was not secondary to changes in gastric blood flow. Mechanisms mediating the cytoprotective effects of SCH 28080 were investigated. SCH 28080 (10 mg/kg p.o.) increased total mucus as determined by measurements of N-acetylneuraminic acid in rat stomach. In the isolated guinea-pig gastric mucosa, bicarbonate secretion was augmented in a dose-dependent (10(-6)-10(-4) M) manner. Concomitant stimulation of the gastric mucus and bicarbonate by SCH 28080 may lead to strengthening of the gastric mucosal barrier and account for its gastric cytoprotective activity against injuring agents. In conclusion, the antisecretory and cytoprotective activities of SCH 28080 are due to a direct action on the parietal cells and a stimulatory effect on mucus and bicarbonate secretion by the mucosal epithelial cells, respectively.