Time-dependent aggravation or attenuation of lipopolysaccharide-induced gastric injury by nitric oxide synthase inhibition

J Surg Res. 2005 Dec;129(2):265-71. doi: 10.1016/j.jss.2005.05.010. Epub 2005 Jul 18.


Background: This study was conducted to test the hypothesis that nonselective nitric oxide synthase (NOS) inhibitors have different effects on lipopolysaccharide (LPS)-induced gastric injury depending upon whether they are given concurrently with LPS or after LPS at a time point that inducible NOS is up-regulated.

Materials and methods: Female Sprague-Dawley rats received intraperitoneal (IP) LPS (20 mg/kg) for 3 h. Western immunoblot was used to determine iNOS, eNOS, and nNOS immunoreactivity after 3 h. In an additional set of experiments, we assessed the time dependent effects of nitric oxide synthase inhibition by giving rats LPS (20 mg/kg, IP) concurrently with Nitro-l-arginine methyl ester (l-NAME; 2-5 mg/kg, SC) or l-N(G)-(1-iminoethyl) lysine (l-NIL; 10 mg/kg, IP) for 5 h or LPS and delayed administration of l-NAME or l-NIL 3 h following LPS injection in identical doses. For these NOS inhibition experiments microscopic and macroscopic injury was assessed by a blinded observer using previously published scoring systems. Injury studies were conducted by exposing the stomach to 3 ml of 5 mM acidified taurocholate for 5 minutes in an anesthetized prep.

Results: A 3-h treatment with LPS (20 mg/kg IP) significantly increased iNOS protein immunoreactivity (Western immunoblot) but not eNOS or nNOS. N(G)-l-NAME (2-5 mg/kg SC) dose dependently aggravated macroscopic (computerized planimetry) and morphological gastric injury caused by the intraluminal bile irritant 5 mm acidified taurocholate for 10 min when given concurrently with LPS, an effect reversed by l- but not D-arginine (300 mg/kg). In contrast, delayed administration of l-NAME (3 h after LPS) dose dependently attenuated the ability of LPS to exacerbate gastric injury from bile. Both concurrent and delayed administration of the selective iNOS inhibitor, l-NIL (10 mg/kg IP) attenuated the effects of LPS.

Conclusions: These data indicate that during endotoxemia, the stomach is rendered more susceptible to damage from luminal irritants such as bile, a frequent occurrence in septic patients with a gastrointestinal ileus. In this setting, iNOS has a pathologic role while the constitutive NOS isoforms play gastroprotective roles.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Gastric Juice / metabolism*
  • Lipopolysaccharides / pharmacology
  • Lysine / analogs & derivatives
  • Lysine / pharmacology
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology*
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type I / antagonists & inhibitors
  • Nitric Oxide Synthase Type I / metabolism
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism
  • Nitric Oxide Synthase Type III / antagonists & inhibitors
  • Nitric Oxide Synthase Type III / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Shock, Septic / drug therapy*
  • Shock, Septic / metabolism
  • Stomach / enzymology
  • Stomach Diseases / drug therapy*
  • Stomach Diseases / metabolism
  • Time Factors


  • Enzyme Inhibitors
  • Lipopolysaccharides
  • N(6)-(1-iminoethyl)lysine
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos2 protein, rat
  • Lysine
  • NG-Nitroarginine Methyl Ester