Abstract
Backgrounds and Aims: We examined the effect of various prostaglandin E (PGE) analogs specific to EP receptor subtypes on indomethacin-induced gastric lesions in rats and investigated which EP receptor subtype is involved in the protective action of PGE<sub>2</sub> using EP-receptor knockout mice. Methods: Gastric lesions were induced by subcutaneous administration of indomethacin (35 mg/kg). Gastric motility was measured using a balloon method, while neutrophil chemotaxis determined using a Boyden chamber. Results: Indomethacin-induced gastric lesions were significantly prevented by PGE<sub>2</sub> as well as atropine, and the former effect was mimicked by sulprostone (EP<sub>1</sub>/EP<sub>3</sub>) and 17-phenyl PGE<sub>2</sub> (EP<sub>1</sub>) and antagonized by an EP<sub>1</sub> antagonist, ONO-AE-829. Neither butaprost (EP<sub>2</sub>), ONO-NT-012 (EP<sub>3</sub>) nor 11-deoxy PGE<sub>1</sub> (EP<sub>3</sub>/EP<sub>4</sub>) showed any protection on the lesions. Indomethacin caused a marked increase in gastric motility; the response preceded the onset of lesions and was inhibited by atropine as well as PGE derivatives acting as EP<sub>1</sub> receptors. Neutrophil chemotaxis was inhibited by PGE<sub>2</sub>, butaprost and slightly by 11-deoxy PGE<sub>1</sub>, but not by either 17-phenyl PGE<sub>2</sub>, ONO-NT-012 or atropine. In addition, indomethacin caused damage similarly in both wild-type and knockout mice lacking EP<sub>1</sub> or EP<sub>3</sub> receptors, yet the protective action of PGE<sub>2</sub> was observed in wild-type and EP<sub>3</sub> receptor knockout mice but totally disappeared in mice lacking EP<sub>1</sub> receptors. Conclusion: PGE<sub>2</sub> inhibits indomethacin-induced gastric lesions, through EP<sub>1</sub> receptors, and this effect may be functionally associated with inhibition of gastric motility but not of neutrophil activation/migration.
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