Abstract
The role of nitric oxide (NO) synthase inhibitors in indomethacin (INDO) -induced enteropathy was investigated in male Sprague-Dawley rats. Rats were subcutaneously administered 5% sodium bicarbonate (controls), two doses of INDO 7.5 mg/kg, and three different inducible NO synthase (iNOS) inhibitors at various concentrations 24 hr, apart; aminoguanidine (AG), guanidinoethyldisulfide (GED), and n-(3-aminomethyl)benzylacetamidine (1400W). Rats were killed four days after the initial injection and small intestinal mucosa was assayed for myeloperoxidase (MPO) activity and iNOS expression by western blot analysis. Serum nitrite/nitrate (NOx) concentration was measured colorimetrically. INDO produced acute ulcers along the mesenteric border from the ileum to proximal jejunum. Rats treated with AG (25 and 50 mg/kg), GED (2.5 mg/kg), and 1400W (0.1 mg/kg) showed decreased total ulcer length and MPO activity by 51, 72, 53, and 61% and by 58, 88, 68, and 70%, respectively, compared to INDO alone. All inhibitors similarly reduced INDO-enhanced serum NOx concentrations to its basal levels. Significant iNOS expression was detected in INDO-treated rats, but the inhibitors did not alter iNOS expression. Our data suggest that NO derived from iNOS may be a key factor in the pathogenesis of acute INDO-induced enteropathy in rats.
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REFERENCES
Miller MJS, Thompson JH, Zhang XJ, Sadowska-Krowica H, Kakkis JL, Munshi UK, Sandoval M, Rossi JL, Eloby-Childress S, Beckman JS, Ye YZ, Rodi CP, Manning PT, Currie MG, Clark DA: Role of inducible nitric oxide synthase expression and peroxynitrite formation in guinea pig ileitis. Gastroenterology 109:1475–1483, 1995
Billiar TR, Harbrecht BG: Resolving the nitric oxide paradox in acute tissue damage. Gastroenterology 113:1405–1407, 1997
Miller MJS, Sandoval M: Nitric oxide III. A molecular prelude to inflammation. Am J Physiol 276(Gastrointest Liver Physiol 39):G795–G799, 1999
Guslandi M: Nitric oxide and inflammatory bowel diseases. Eur J Clin Invest 28:904–907, 1998
Rachmilewitz D, Karmelli F, Okon E, Bursztyn M: Experimental colitis is ameliorated by inhibition of nitric oxide synthase activity. Gut 37:247–255, 1995
Miller MJS, Sandoval M: Nitric Oxide 1. Physiological chemistry of nitric oxide and its metabolite: Implications in inflammation. Am J Physiol 276(Gastrointest Liver Physiol 39):G315–G321, 1999
Muscara MN, Wallace JL: Nitric oxide. V. Therapeutic potential of nitric oxide donors and inhibitors. Am J Physiol 276(Gastrointest Liver Physiol 39):G1313–G1316, 1999
Rachimilewitz D, Stamler JS, Bachwich D, Karmeli F, Ackerman Z, Podolsky DK: Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn' disease. Gut 36:718–723, 1994
Chen K, Hirota S, Wasa M, Okada A: Expression of NOS II and its role in experimental small bowel ulceration in rats. Surgery 126:553–561, 1999
Veerabagu MP, Opara EI, Meguid MM, Nandi J, Oler A, Holtzapple PG, Levine RA: Mode of food intake reduction in Lewis rats with indomethacin-induced ulcerative ileitis. Physiol Behav 60:381–387, 1996
Veerabagu MP, Meguid MM, Oler A, Levine RA: Intravenous nucleoside and a nucleotide promote healing of small bowel ulcers in experimental enterocolitis. Dig Dis Sci 41:1452–1457, 1996
Tanaka A, Kunikata T, Mizoguchi H, Kato S, Takeuchi K: Dual action of nitric oxide in pathogenesis of indomethacininduced small intestinal ulceration in rats. J Physiol Pharmacol 50:405–417, 1999
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
Laszlo F, Whittle BJR: Role of nitric oxide and plateletactivating factor in the initiation of indomethacin-provoked intestinal inflammation in rats. Eur J Pharmacol 344:191–195, 1998
Whittle BJR, Laszlo F, Evans SM, Moncada S: Induction of nitric oxide synthase and microvascular injury in the rat jejunum provoked by indomethacin. Br J Pharmacol 116:2286–2229, 1995
Bjarnasson I, Hayllar J, Mac Pherson AJ, Russel AS: Side effects of nonsteroid antiinflammatory drugs on the small and large intestine in humans. Gastroenterology 104:1832–1847, 1993
Garvey EP, Oplinger JA, Furfines ES, Kiff RJ, Laszlo F, Whittle BJ, Knowles RG: 1400W is a slow, tight binding, and highly selective inhibitor of inducible nitric-oxide synthase in vitro and in vivo. J Biol Chem 272:4959–4963, 1997
Stenger S, Thuring H, Rollinghoff M, Manning P, Bogdan C: L-N 6-(1-iminoethyl)-lysine potently inhibits inducible nitric oxide synthase and is superior to N G-mono-methyl-arginine in vitro and in vivo. Eur J Pharmacol 294:703–712, 1995.
Grisham MB, Benoit JN, Granger DN: Assessment of leukocyte involvement during ischemia and reperfusion of intestine. Methods Enzymol 186:729–742, 1996
Rachmilewitz D, Stamler JS, Karmeli F, Mullins ME, Singel DJ, Loscalzo J, Xavier RJ, Podolsky DK: Peroxynitrite-induced rat colitis: A new model of colonic inflammation. Gastroenterology 105:1681–1688, 1993
Reuter KB, Davies NM, Wallace JL: Nonsteroidal antiinflammatory drug enteropathy in rats: Role of permeability, bacteria and enterohepatic circulation. Gastroenterology 112:109–117, 1997
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Parasher, G., Frenklakh, L., Goodman, D. et al. Nitric Oxide Inhibitors Ameliorate Indomethacin-Induced Enteropathy in Rats. Dig Dis Sci 46, 2536–2541 (2001). https://doi.org/10.1023/A:1012304710187
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DOI: https://doi.org/10.1023/A:1012304710187