Abstract
We investigated the functional mechanisms underlying the expression of inducible nitric oxide (NO) synthase (iNOS) in the rat small intestine following the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and found a correlation with the intestinal ulcerogenic properties of NSAIDs. Conventional NSAIDs (indomethacin, dicrofenac, naproxen, and flurbiprophen), a selective cyclooxygenase (COX)-1 inhibitor (SC-560) and a selective COX-2 inhibitor (rofecoxib) were administered p.o., and the intestinal mucosa was examined 24 hours later. Indomethacin decreased prostaglandin E2 (PGE2) production in the intestinal mucosa and caused intestinal hypermotility and bacterial invasion as well as the upregulation of iNOS expression and NO production, resulting in hemorrhagic lesions. Other NSAIDs similarly inhibited PGE2 production and caused hemorrhagic lesions with intestinal hypermotility as well as iNOS expression. Hypermotility in response to indomethacin was prevented by both PGE2 and atropine but not ampicillin, yet all these agents inhibited not only bacterial invasion but also expression of iNOS as well, resulting in prevention of intestinal lesions. SC-560, but not rofecoxib, caused a decrease in PGE2 production, intestinal hypermotility, bacterial invasion, and iNOS expression, yet this agent neither increased iNOS activity nor provoked intestinal damage because of the recovery of PGE2 production owing to COX-2 expression. Food deprivation totally attenuated both iNOS expression and lesion formation in response to indomethacin. In conclusion, the expression of iNOS in the small intestine following administration of NSAIDs results from COX-1 inhibition and is functionally associated with intestinal hypermotility and bacterial invasion. This process plays a major pathogenic role in the intestinal ulcerogenic response to NSAIDs.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Robert A, Asano T: Resistance of germ-free rats to indomethacin-induced intestinal inflammation. Prostaglandins 14:333–341, 1987
Fang WF, Broughton A, Jacobson ED: Indomethacin induced intestinal inflammation. Am J Dig Dis 22:749–760, 1977
Bjarnason I, Zanelli G, Smith T, et al.: Nonsteroidal anti-inflammatory drug-induced intestinal inflammation in humans. Gastroenterology 93:480–489, 1987
Weissenborn U, Maedge S, Buettner D, Sewing KF: Indomethacin-increased gastrointestinal lesions in relation to tissue concentration, food intake and bacterial invasion in the rat. Pharmacology 30:32–39, 1985
Whittle BJR: Temporal relationship between cyclooxygenase inhibition, as measured by prostacyclin biosynthesis, and the gastrointestinal damage induced by indomethacin in the rat. Gastroenterology 80:94–98, 1981
Whittle BJR, Laszlo F, Evans AM, Moncada S: Inducible nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin. Br J Pharmacol 116:2286–2290, 1995
Wallace JL, McKnight W, Reuter BK, Vergnolle N: NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 119:706–714, 2000
Gretzer B, Maricic N, Respondek M, Schuligoi R, Peskar BM: Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge. Br J Pharmacol 132:1565–1573, 2001
Takeuchi K, Tanaka A, Suzuki K, Mizoguchi H, Araki H: Gastrointestinal sparing anti-inflammatory drugs: effects on ulcerogenic and healing responses. Current Pharmaceutical Design 7:49–71, 2001
Tanaka A, Araki H, Hase S, Komoike Y, Takeuchi K: Inhibition of both COX-1 and COX-2 is required for development of gastric damage in response to nonsteroidal antiinflammatory drugs. J Physiol Paris 95:21–27, 2001
Tanaka A, Hase S, Miyazawa T, Takeuchi K: Up-regulation of COX-2 by inhibition of COX-1: A key to NSAID-Induced intestinal damage. J Pharmacol Exp Ther 300:754–761, 2002
Boughton-Smith N, Evans SM, Laszlo F, Whittle BJR, Moncada S: The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat. Br J Pharmacol 110:1189–1195, 1993
Konaka A, Nishijima M, Tanaka A, Kunikata T, Kato S, Takeuchi K: Nitric oxide, superoxide radicals and mast cells in Pathogenesis of indomethacin-induced small intestinal lesions in rats. J Physiol Pharmacol 50:25–38, 1999
Tanaka A, Kunikata T, Konaka A, Kato S, Takeuchi K: Dual action of nitric oxide in pathogenesis of indomethacin-induced small intestinal ulceration in rats. J Physiol Pharmacol 50:405–417, 1999
Takeuchi K, Miyazawa T, Tanaka A, Kato S, Kunikata T: Pathogenic importance of intestinal hypermotility in NSAID-induced small intestinal damage in rats. Digestion 66:30–41, 2002
Smith CJ, Zhang Y, Koboldt CM, et al.: Pharmacological analysis of cyclooxygenase-1 in inflammation. Proc Natl Acad Sci USA 95:13313–13318, 1998
Chan CC, Boyce S, Bridear C, et al.: Pharmacology of a selective cyclooxygenase-2 inhibitor L-745,337: a novel non-steroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and non-human primate stomach. J Pharmacol Exp Ther 274:1531–1537, 1995
Futaki N, Takahashi S, Yokoyama M, Arai I, Higuchi S, Otomo S: NS-398, a new antiinflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclo-oxygenase (COX-2) activity in vitro. Prostaglandins 47:55–59, 1994
Tanaka A, Hase S, Miyazawa T, Ohno R, Takeuchi K: Role of COX-1 and COX-2 inhibition in NSAID-induced intestinal damage in rats: relation to various pathogenic events. J Pharmacol Exp Ther 303:1248–1254, 2002
Feng L, Sun W, Xia Y, et al.: Cloning two isoforms of rat cyclooxygenase: Differential regulation of their expression. Arch Biochem Biophys 307:361–368, 1993
Kunikata T, Umeda M, Tanaka A, Kato S, Takeuchi K: 16,16-dimetyl prostaglandin E2 inhibits indomethacin-induced small intestinal lesions through EP3 and EP4 receptors. Dig Dis Sci 47:894–904, 2002
Brown JF, Tepperman BL, Hanson PJ, Whittle BJR, Moncada S: Differential distribution of nitric oxide synthase between cell fractions isolated from the rat gastric mucosa. Biochem Biophys Res Comm 184:680–685, 1992
Green LC, Tannebaum SR, Goldman P: Nitrite synthesis in the germ free and conventional rat. Science 212:56–58, 1981
Reuter BK, Davies NM, Wallace JL: Nonsteroidal anti-inflammatory drug enteropathy in rats: role of permeability, bacteria, and enterohepatic circulation. Gastroenterology 112:109–117, 1997
Tanaka A, Matsumoto M, Hayashi Y, Takeuchi K: Functional mechanism underlying cyclooxygenase-2 expression in rat small intestine following administration of indomethacin: relation to intestinal hypermotility. J Gastroenterol Hepatol 20:38–45, 2005
Bertrand V, Guimbaud R, Tulliez M, et al.: Increase in tumor necrosis factor-α production linked to the toxicity of indomethacin for the rat small intestine. Br J Pharmacol 124:1385–1394, 1998
Konaka A, Nishijima M, Tanaka A, Kato S, Takeuchi K: Roles of enterobacteria, nitric oxide and neutrophil in pathogenesis of indomethacin-induced small intestinal lesions in rats. Pharmacol Res 40:517–524, 1999
Evans SM, Whittle BJ: Interactive roles of superoxide and inducible nitric oxide synthase in rat intestinal injury provoked by non-steroidal anti-inflammatory drugs. Eur J Pharmacol 429:287–96, 2003
Mizoguchi H, Miyazawa T, Ogawa Y, Tanaka A, Kato S, Takeuchi K: Protective effect of rebamipide on indomethacin-induced intestinal damage in rats. J Gastroent Hepatol 16:1112–1119, 2001
Lamarque D, Nhieu JT, Breban M, et al.: Lymphocytic infiltration and expression of inducible nitric oxide synthase in human duodenal and colonic mucosa is a characteristic feature of ankylosing spondylitis. J Rheumatol 30:2428–2436, 2003
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takeuchi, K., Yokota, A., Tanaka, A. et al. Factors Involved in Upregulation of Inducible Nitric Oxide Synthase in Rat Small Intestine Following Administration of Nonsteroidal Anti-inflammatory Drugs. Dig Dis Sci 51, 1250–1259 (2006). https://doi.org/10.1007/s10620-006-8045-4
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s10620-006-8045-4