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The effects of a nitric oxide (NO) releasing derivative of indomethacin (NCX-530) on gastric ulcerogenic and healing responses were evaluated in rats and mice, in comparison with the parent compound indomethacin. Indomethacin (per os) produced damage in the rat stomach in a dose-dependent manner. NCX-530 (per os) itself, however, was not ulcerogenic and even showed a dose-dependent protection against HCl/ethanol-induced lesions in the rat stomach. Likewise, indomethacin given repeatedly delayed healing of gastric ulcers induced in mice by thermal cauterization, while NCX-530 did not affect the healing response and significantly promoted the healing as compared to indomethacin. These actions of NCX-530 were mimicked by the combined administration of a NO donor NOR-3 with indomethacin. The amount of NO metabolites was increased in both the gastric contents and serum when NCX-530, but not indomethacin, was given in pylorus-ligated stomachs. Neither indomethacin nor NCX-530 influenced gastric acid secretion and transmucosal potential difference, yet NCX-530 caused a marked increase of gastric mucosal blood flow, which was preventable by carboxy-PTIO, a scavenger of NO. Gastric motility was increased by indomethacin but not by NCX-530. In addition, NCX-530 inhibited PGE2 generation in both the intact and ulcerated gastric mucosa and showed antiinflammatory action on carrageenan-induced rat paw edema, as effectively as indomethacin. These results suggest that unlike indomethacin, NCX-530 caused neither an irritating action on the stomach nor healing impairment effect on the preexisting gastric ulcers, but conferred gastric protection against HCl/ethanol, despite causing cyclooxygenase inhibition and antiinflammatory action, as effectively as indomethacin. This NO-releasing indomethacin, probably by releasing NO, exerts protective influences, such as an increase of gastric mucosal blood flow, that counteract the potential damaging effects of cyclooxygenase inhibition by indomethacin.