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 (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.
Takeuchi
K
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Japan.
Mizoguchi
H
H
Araki
H
H
Komoike
Y
Y
Suzuki
K
K
D000085:Acetates / Q000633:toxicity*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007211:Indoles / Q000633:toxicity*; D007213:Indomethacin / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects* / Q000503:physiopathology; D013276:Stomach Ulcer / Q000139:chemically induced / Q000473:pathology
C420084:1-(4-chlorobenzoyl)-5-methoxy-2-1H-indole-3-acetic acid 3-(nitrooxymethyl)phenyl ester; D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009569:Nitric Oxide; C061872:FK 409; D007213:Indomethacin