Interactive roles of superoxide and inducible nitric oxide synthase in ratintestinal injury provoked by non-steroidal anti-inflammatory drugs

The role of nitric oxide (NO) formed by inducible NO synthase (iNOS), super oxide and the lipopolysaccharide from luminal bacteria in non-steroidal ant i-inflammatory drug-induced intestinal injury was investigated in the rat. Administration (s.c. or p.o.) of indomethacin (10 mg kg(-1)), flurbiprofen (40 mg kg(-1)) or diclofenac (40 mg kg(-1)) increased the vascular leakage of radiolabelled albumin in the jejunum, determined after 24 h, associated with the induction of iNOS, assessed by the conversion of radiolabelled L-a rginine. Pre-treatment with ampicillin(200 mg kg(-1) day(-1), p.o,), metron idazole(200 mg kg(-1) day(-1), p.o.), or polymixin B (15 mg kg(-1) day(-1), S.C.), inhibited indomethacin-induced lesion formation, reduced microvascu lar leakage and prevented the expression of iNOS activity. Administration o f the highly selective iNOS inhibitor, GW273629 ((R)-2-amino-4,4-dioxo-6(1- iminioethylamino)-4-thiahexanoic acid; 5 me kg(-1), s.c.), 18 h after indom ethacin, likewise prevented the intestinal lesions and attenuated the micro vascular leakage. Superoxide dismutase conjugated with polyethylene glycol (3000 U kg(-1), i.v.), inhibited the indomethacin-induced lesions and micro vascular leak-age, but not the expression of iNOS activity. These findings suggest that non-steroidal anti-inflammatory drugs compromise mucosal integ rity, leading to luminal bacterial translocation. This provokes iNOS induct ion, leading to microvascular injury involving both NO and superoxide. (C) 2001 Elsevier Science B.V. All rights reserved.