We examined the role of prostaglandin E (EP) receptor subtypes in the regulation of gastric acid secretion in the rat. Under urethane anesthesia, the stomach was superfused with saline, and the acid secretion was determined at pH 7.0 by adding 50 mM NaOH. The acid secretion was stimulated by intravenous infusion of histamine or pentagastrin. Various EP agonists were administered intravenously, whereas EP antagonists were given subcutaneously 30 min or intravenously 10 min before EP agonists. PGE(2) suppressed the acid secretion stimulated by either histamine or pentagastrin in a dose-dependent manner. The acid inhibitory effect of PGE(2) was mimicked by sulprostone (EP(1)/EP(3) agonist) but not butaprost (EP(2) agonist) or AE1-329 (EP(4) agonist). The inhibitory effect of sulprostone, which was not affected by ONO-8711 (EP(1) antagonist), was more potent against pentagastrin- (50% inhibition dose: 3.6 mug/kg) than histamine-stimulated acid secretion (50% inhibition dose: 18.0 mug/kg). Pentagastrin increased the luminal release of histamine, and this response was also inhibited by sulprostone. On the other hand, AE1-329 (EP(4) agonist) stimulated the acid secretion in vagotomized animals with a significant increase in luminal histamine. This effect of AE1-329 was totally abolished by cimetidine as well as AE3-208 (EP(4) antagonist). These results suggest that PGE(2) has a dual effect on acid secretion: inhibition mediated by EP(3) receptors and stimulation through EP(4) receptors. The former effect may be brought about by suppression at both parietal and enterochromaffin-like cells, whereas the latter effect may be mediated by histamine released from enterochromaffin-like cells.