Low direct cytotoxicity and cytoprotective effects of nitric oxide releasing indomethacin.
Nitric oxide (NO) releasing non-steroidal anti-inflammatory drugs (NSAIDs) have shown a marked reduction of gastrointestinal side effects and we here examined the cytotoxicity of NCX 530 (NO-indomethacin). Under conditions where indomethacin clearly induced both necrosis and apoptosis, NCX 530 induced neither. NCX 530 protected cells from celecoxib-induced necrosis and apoptosis. NCX 530 partially suppressed celecoxib-dependent membrane permeabilization and an inhibitor for guanylate cyclase suppressed the cytoprotective effect of NCX 530 against celecoxib. In vivo, NCX 530 alone produced fewer gastric lesions in rats than did indomethacin. A combination of the oral administration of celecoxib together with the intraperitoneal administration of indomethacin, but not of NCX 530, clearly resulted in the production of gastric lesions. The low direct cytotoxicity and the cytoprotective effect of NCX 530 observed in vitro may also act in vivo, thus ensuring that NCX 530 is safe for use on the gastric mucosa.
Tomisato
Wataru
W
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, 862-0973.
Tanaka
Ken-Ichiro
K
Tsutsumi
Shinji
S
Hoshino
Tatsuya
T
Yokomizo
Kazumi
K
Suzuki
Keitarou
K
Katsu
Takashi
T
Mizushima
Tohru
T
Mizushima
Tohru
T
D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D005753:Gastric Mucosa / Q000166:cytology* / Q000187:drug effects*; D006168:Guinea Pigs; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013270:Stomach / Q000187:drug effects*
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; D007213:Indomethacin