Effect of NOS inhibition on rat gastric matrix metalloproteinase production during endotoxemia

Shock. 2006 May;25(5):507-14. doi: 10.1097/01.shk.0000209543.83929.bd.


Matrix metalloproteinases (MMPs) degrade the extracellular matrix and contribute to LPS-induced gastric injury. MMPs are closely modulated by their activators, membrane type-MMP (MT-MMPs) and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). As LPS-induced gastric injury is mediated in part by iNOS, and NO modulates MMP production in vitro, we hypothesized that NOS inhibition would similarly modulate LPS-induced gastric MMP production. Therefore, the purpose of these studies was to compare the effects of selective and nonselective NOS inhibition on LPS-induced gastric MMP production.

Methods: Sprague-Dawley rats were given either the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 5 mg/kg, s.c.), a selective iNOS inhibitor, aminoguanidine (45 mg/kg, i.p.) or L-N-iminoethyl-lysine (L-NIL; 10 mg/kg, i.p.), or vehicle 15 min before saline or LPS (20 mg/kg, i.p.) and killed 24 h after LPS administration. Stomachs were assessed for macroscopic injury (computed planimetry), and gastric mucosal MMP production was assessed by gelatin zymography, in situ zymography, and Western analysis for MMP-2, MT1-MMP, and TIMP-2. (n > or = 4/group; ANOVA).

Results: Aminoguanidine treatment decreased LPS-induced macroscopic gastric injury as well as MMP-2 and MT1-MMP protein production while having no effect on TIMP-2 protein levels. L-NIL similarly attenuated the induction of MMP-2 and MT1-MMP by LPS. L-NAME failed to attenuate LPS induced gastric injury or MT1-MMP protein induction and increased MMP-2 levels. L-NAME similarly had no effect on gastric TIMP-2 production.

Conclusions: Selective iNOS inhibition decreases gastric MMP-2 activity after LPS administration, whereas nonselective inhibition increases MMP-2 levels. The ability of selective iNOS inhibition to ameliorate LPS-induced gastric injury may be due in part to its inhibition of active MMP-2 production, whereas nonselective NOS inhibitors increase MMP-2 levels and maintain gastric injury after LPS administration.

Publication types

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

MeSH terms

  • Animals
  • Endotoxemia / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Matrix / metabolism
  • Female
  • Gastric Mucosa / enzymology*
  • Gelatinases / metabolism
  • Lipopolysaccharides / chemistry
  • Lipopolysaccharides / metabolism
  • Matrix Metalloproteinase 2 / biosynthesis*
  • Matrix Metalloproteinase 2 / chemistry
  • Models, Biological
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Nitric Oxide Synthase Type II
  • Gelatinases
  • Matrix Metalloproteinase 2
  • NG-Nitroarginine Methyl Ester