Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats.
The concept that gastroprotection by agents such as mild irritants, antacids, or sucralfate is prostaglandin (PG)-mediated has been challenged recently. These agents do not reproducibly stimulate prostaglandin formation, and indomethacin does not effectively attenuate their protective potency. Rebamipide is a novel antiulcer compound. This study was designed to clarify whether eicosanoids contribute to the gastroprotective activity of the drug. In the rat stomach, rebamipide (100 and 500 mg/kg, intraperitoneally) slightly increased release of PGE2, 6-keto-PGF1 alpha, thromboxane B2, and the metabolite 15-keto-13,14-dihydro-PGE2 from mucosal fragments incubated ex vivo and significantly enhanced secretion of these products into the lumen, resulting in gastric juice eicosanoid levels exceeding those in controls several-fold. Mucosal formation of leukotriene (LT) C4 was not affected by rebamipide. Rebamipide caused substantial protection against gastric damage produced by ethanol, which was antagonized by pretreatment with indomethacin (0.1-5 mg/kg, subcutaneously). The dose-response relationship of indomethacin for inhibition of prostaglandin formation and rebamipide-induced protection correlated well and 5 mg/kg indomethacin completely prevented the protective effect of rebamipide. The results indicate that: (1) in contrast to most other protective agents, protection by rebamipide involves the endogenous prostaglandin system; (2) the increase in prostaglandin formation results from stimulation of biosynthesis, and not inhibition of degradation; (3) gastroprotection by rebamipide occurs despite increased thromboxane formation and is not associated with reduced generation of LTC4; and (4) determinations of gastric juice eicosanoids seem to be particularly useful to evaluate effects of agents increasing formation of cyclooxygenase products in the stomach.
Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Germany.
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Kleine
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Kluge
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Peskar
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005750:Gastric Juice / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D011453:Prostaglandins / Q000096:biosynthesis*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000378:metabolism
D000897:Anti-Ulcer Agents; D011453:Prostaglandins; D015363:Quinolones; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D015232:Dinoprostone; C052785:rebamipide; D000409:Alanine; D007213:Indomethacin