Dual action of nitric oxide in pathogenesis of indomethacin-induced small intestinal ulceration in rats.
We investigated the pathogenic role of nitric oxide (NO) in indomethacin-induced intestinal ulceration in rats. Nonfasting animals responded to a single administration of indomethacin (10 mg/kg, s.c.), resulting in multiple hemorrhagic lesions in the small intestine, mostly the jejunum and ileum. The damage was first observed 6 hr after indomethacin, the severity increasing progressively with time up to 24 hr later, accompanied with the gene expression of inducible NO synthase (iNOS) and the increase of nitrite and nitrate (NOx) contents in the mucosa. The ocurrence of damage was significantly prevented when iNOS induction was inhibited by dexamethasone given either once 0.5 hr before or twice 0.5 hr before and 6 hr after indomethacin. Likewise, aminoguanidine (a relatively selective iNOS inhibitor) reduced the severity of damage, irrespective whether given twice or as a single injection 6 hr after indomethacin. By contrast, the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) exhibited a biphasic effect, depending on the time of administration; the pre-administration worsened the damage, while the later administration reduced the severity of these lesions, yet both responses occureed in a L-arginine-sensitive manner. Pre-administration of L-NAME, but not aminoguanidine, significantly decreased NOx production in the intestinal mucosa of normal rats, while the increase of NOx production following indomethacin was significantly suppressed by the later administration of aminoguanidine as well as L-NAME. These results suggest that NO exerts a dual action in the pathogenesis of indomethacin-induced intestinal ulceration; NO generated by cNOS is protective against indomethacin, by maintaining the integrity of intestinal mucosa, while NO derived by iNOS plays a key pathogenic role in the ulcerogenic process.
Tanaka
A
A
Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan.
Kunikata
T
T
Mizoguchi
H
H
Kato
S
S
Takeuchi
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D007077:Ileal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D007213:Indomethacin / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007579:Jejunal Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D006146:Guanidines; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin