Nitric oxide inhibitors ameliorate indomethacin-induced enteropathy in rats.
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.
Parasher
G
G
Department of Medicine, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Frenklakh
L
L
Goodman
Siddiqui
T
T
Nandi
J
J
Levine
R A
RA
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D007213:Indomethacin; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000517:prevention & control; D007413:Intestinal Mucosa / Q000201:enzymology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014456:Ulcer / Q000139:chemically induced* / Q000517:prevention & control
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D006146:Guanidines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; C014363:bis(2-guanidinoethyl)disulfide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine; D007213:Indomethacin