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

Eur J Pharmacol. 2001 Oct 19;429(1-3):287-96. doi: 10.1016/s0014-2999(01)01327-9.


The role of nitric oxide (NO) formed by inducible NO synthase (iNOS), superoxide and the lipopolysaccharide from luminal bacteria in non-steroidal anti-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-arginine. Pre-treatment with ampicillin (200 mg kg(-1) day(-1), p.o.), metronidazole (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 microvascular leakage and prevented the expression of iNOS activity. Administration of the highly selective iNOS inhibitor, GW273629 ((R)-2-amino-4,4-dioxo-6(1-iminioethylamino)-4-thiahexanoic acid; 5 mg kg(-1), s.c.), 18 h after indomethacin, likewise prevented the intestinal lesions and attenuated the microvascular leakage. Superoxide dismutase conjugated with polyethylene glycol (3000 U kg(-1), i.v.), inhibited the indomethacin-induced lesions and microvascular leakage, but not the expression of iNOS activity. These findings suggest that non-steroidal anti-inflammatory drugs compromise mucosal integrity, leading to luminal bacterial translocation. This provokes iNOS induction, leading to microvascular injury involving both NO and superoxide.

MeSH terms

  • Ampicillin / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Capillary Permeability / drug effects
  • Enzyme Activation / drug effects
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / pharmacology
  • Gentian Violet
  • Indomethacin / pharmacology
  • Intestinal Mucosa / drug effects*
  • Intestinal Mucosa / enzymology
  • Intestinal Mucosa / pathology*
  • Jejunum / drug effects
  • Jejunum / enzymology
  • Jejunum / pathology
  • Male
  • Metronidazole / pharmacology
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase / physiology*
  • Nitric Oxide Synthase Type II
  • Phenazines
  • Polymyxin B / pharmacology
  • Rats
  • Rats, Wistar
  • Sulfones / pharmacology
  • Superoxide Dismutase / pharmacology
  • Superoxides


  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • GW 273629
  • Gram's stain
  • Phenazines
  • Sulfones
  • Superoxides
  • Metronidazole
  • Ampicillin
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Superoxide Dismutase
  • Polymyxin B
  • Gentian Violet
  • Indomethacin