Lack of small intestinal ulcerogenecity of nitric oxide-releasing indomethacin, NCX-530, in rats.
OBJECTIVE
To evaluate the intestinal ulcerogenic property of nitric oxide-releasing indomethacin (NCX-530) in the rat, in comparison with indomethacin.


METHODS
Animals were given indomethacin or NCX-530 subcutaneously and killed 24 h later for macroscopic examination of the small intestine.


RESULTS
A single administration of indomethacin (10 mg/kg) provoked damage, mainly in the jejunum and ileum, accompanied by an increase in myeloperoxidase and inducible nitric oxide synthase activities as well as bacterial translocation. NCX-530 at an equimolar dose (14.2 mg/kg) caused no gross damage in the small intestine, nor any significant change in inducible nitric oxide synthase and myeloperoxidase activities or bacterial translocation. NOR-3, the nitric oxide donor (6.0 mg/kg), when administered subcutaneously together with indomethacin, significantly prevented the occurrence of intestinal lesions and other mucosal changes. Indomethacin reduced mucus and fluid secretions in the small intestine, while both NCX-530 and NOR-3 enhanced these secretions. NCX-530 reduced the mucosal prostaglandin E2 contents and exhibited an anti-inflammatory action against carrageenan-induced paw oedema, with equal effectiveness to indomethacin.


CONCLUSIONS
NCX-530 does not cause intestinal damage, despite inhibiting cyclooxygenase activity. The reduced intestinal toxicity of NCX-530 may be attributable to inhibition of enterobacterial translocation, partly by increasing the mucus and fluid secretions mediated by nitric oxide released from this compound.
Mizoguchi
H
H
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Hase
S
S
Tanaka
A
A
Takeuchi
K
K
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018988:Bacterial Translocation / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
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; D009569:Nitric Oxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D007213:Indomethacin