Prostaglandin E inhibits indomethacin-induced gastric lesions through EP-1 receptors.
OBJECTIVE
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(2) 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(2) as well as atropine, and the former effect was mimicked by sulprostone (EP(1)/EP(3)) and 17-phenyl PGE(2) (EP(1)) and antagonized by an EP(1) antagonist, ONO-AE-829. Neither butaprost (EP(2)), ONO-NT-012 (EP(3)) nor 11-deoxy PGE(1) (EP(3)/EP(4)) 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(1) receptors. Neutrophil chemotaxis was inhibited by PGE(2), butaprost and slightly by 11-deoxy PGE(1), but not by either 17-phenyl PGE(2), ONO-NT-012 or atropine. In addition, indomethacin caused damage similarly in both wild-type and knockout mice lacking EP(1) or EP(3) receptors, yet the protective action of PGE(2) was observed in wild-type and EP(3) receptor knockout mice but totally disappeared in mice lacking EP(1) receptors.


CONCLUSIONS
PGE(2) inhibits indomethacin-induced gastric lesions, through EP(1) receptors, and this effect may be functionally associated with inhibition of gastric motility but not of neutrophil activation/migration.
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
K
K
Suzuki
H
H
Araki
H
H
Mizoguchi
O
O
Furukawa
K
K
Takeuchi
D000818:Animals; D015232:Dinoprostone / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000009:adverse effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000502:physiology; D020556:Neutrophil Infiltration / Q000502:physiology; D011458:Prostaglandins E / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D013272:Stomach Diseases / Q000503:physiopathology / Q000517:prevention & control*
D011458:Prostaglandins E; D018078:Receptors, Prostaglandin E; D015232:Dinoprostone; D007213:Indomethacin