Lack of gastric toxicity of nitric oxide-releasing indomethacin, NCX-530, in experimental animals

The effects of a nitric oxide (NO) releasing derivative of indomethacin (NC X-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. NC X-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 ind omethacin. These actions of NCX-530 were mimicked by the combined administr ation of a NO donor NOR-3 with indomethacin. The amount of NO metabolites w as increased in both the gastric contents and serum when NCX-530, but not i ndomethacin, was given in pylorus-ligated stomachs. Neither indomethacin no r NCX-530 influenced gastric acid secretion and transmucosal potential diff erence, 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 inh ibited PGE(2) generation in both the intact and ulcerated gastric mucosa an d showed antiinflammatory action on carrageenan-induced rat paw edema, as e ffectively as indomethacin. These results suggest that unlike indomethacin, NCX-530 caused neither an irritating action on the stomach nor healing imp airment effect on the preexisting gastric ulcers, but conferred gastric pro tection 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.