5-aminosalicylic acid improves indomethacin-induced enteropathy by inhibiting iNOS transcription in rats

Abstract

Nitric oxide has been implicated in the pathogenic mechanism of inflammatory bowel disease states. We evaluated indomethacin-induced enteropathy in rats, in relation to the expression of the inducible isoform of NO synthase (iNOS) using aminosalicylic acid (5-ASA), its isomer 4-ASA (10 or 50 mg/kg/day, po), and dexamethasone, an iNOS transcription inhibitor (3 mg/kg/day, sc). Enteropathy was induced by indomethacin (7.5 mg/kg/day, sc) for two days and the small intestine was examined for lesions over the next 14 days. Indomethacin-induced small-intestinal ulcer size, mucosal myeloperoxidase activity, iNOS expression and serum nitrite/nitrate levels were maximally increased by day 4 and gradually decreased by day 14. Treatment with 5-ASA, but not 4-ASA, decreased indomethacin-induced ulcer length, myeloperoxidase activity, serum nitrite/nitrate levels and iNOS expression at day 4. Dexamethasone had a greater effect than 5-ASA in reducing myeloperoxidase activity and ulcer length by 26 and 32%, respectively. Dexamethasone also reduced serum nitrate/nitrite and iNOS expression to their basal levels. In conclusion, inhibition of iNOS expression by 5-ASA appears to be associated with diminished intestinal ulceration in indomethacin-induced enteropathy.