Role of nitric oxide in indomethacin-induced gastric mucosal dysfunction in the rat

The present study was undertaken to explore the role of nitric oxide (NO) i n the pathogenesis of experimental non-steroidal anti-inflammatory drug (NS AID)-induced gastropathy. We assessed the role of NO inhibition and donatio n in indomethacin-induced gastric mucosal dysfunction. The stomach was perf used with vehicle (control) for 20 min, followed by indomethacin (10 mg ml( -1) in 1.25 % sodium bicarbonate, pH 8.4) for 120 min. N-G-nitro-L-arginine methyl ester (L-NAME, 5 and 10 mg kg(-1), I.V. bolus), L-arginine, D-argin ine (100 mg kg(-1) I.V. bolus, 10 mg kg(-1) h(-1), 2 h infusion) and the NO donor glyceryl trinitrate (GTN) were given at the same time (20, 40 and 80 mu g kg(-1) min(-1), 15 min infusion) as perfusion with indomethacin was s tarted. Epithelial permeability was quantified by measuring blood-to-lumen clearance of Cr-51-labelled EDTA. Indomethacin caused a 20-fold increase in Cr-51-EDTA leakage compared with that of the control group. Treatment with L-NAME or L-arginine did not affect the indomethacin-induced alterations i n mucosal permeability. Administration of GTN (20 mu g kg(-1) min(-1)) sign ificantly reduced the indomethacin-induced mucosal dysfunction. By contrast , higher doses or GTN (80 mu g kg(-1) min(-1)) exacerbated epithelial dysfu nction induced by indomethacin. Elevated levels of carbonyls and myeloperox idase (MPO) observed after indomethacin administration were significantly r educed, to the control values, when GTN (20 mu g kg(-1) min(-1)) was admini stered along with indomethacin. These data suggest that NO from exogenous s ources can exert a dual action on the integrity of the gastric mucosa chall enged by indomethacin. Low doses of GTN can prevent mucosal dysfunction ind uced by indomethacin, while higher doses of GTN may exacerbate the increase s in epithelial permeability.