Effects of chronic nitric oxide synthase inhibition on TNB-induced colitis in rats

J Pharm Pharmacol. 1995 Oct;47(10):827-32. doi: 10.1111/j.2042-7158.1995.tb05749.x.


Nitric oxide (NO) synthesis is increased in ulcerative colitis, but the role of NO in colitis is poorly understood. The present study employed Nw-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats to evaluate the effect of NO on 2,4,6-trinitrobenzenesulphonic acid (TNB)-induced colitis. L-NAME solutions were placed in subcutaneous, osmotic mini-pumps which continuously released L-NAME at 0.042, 0.208, 0.417, or 1.667 mg kg-1 h-1. L-NAME dose-dependently enhanced lesions in TNB-induced colitis. The two higher doses of L-NAME significantly increased colonic mucosal damage, although there was slight, nonsignificant reduced lesion formation with the lowest dose of L-NAME. 0.042 mg kg-1 h-1. A single dose of L-NAME at 100 mg kg-1 subcutaneously injected daily in TNB-treated rats also increased lesions, and these ulcerogenic actions of L-NAME were reversed by L-arginine but not by D-arginine (both at 500 mg kg-1, s.c.). Only the highest dose of L-NAME (mini-pump) significantly depressed myeloperoxidase (MPO) activity. Faecal occult bleeding showed a close relationship with severity of colitis. These findings suggest that there may exist a balance between NO protective and aggressive effects. In TNB-induced colitis, antagonism of endogenous NO generation was intensified, whereas slight inhibition of NO synthesis reduced lesions. Variations in responses, related to timing or dose changes in L-NAME, may reflect the differences in inducible vs constitutive NO synthase isoforms.

MeSH terms

  • Animals
  • Arginine / analogs & derivatives*
  • Arginine / pharmacology
  • Body Weight / drug effects
  • Colitis / chemically induced
  • Colitis / drug therapy*
  • Colitis / enzymology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Infusion Pumps, Implantable
  • Injections, Subcutaneous
  • Intestinal Mucosa / enzymology
  • Male
  • NG-Nitroarginine Methyl Ester
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Peroxidase / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Trinitrobenzenesulfonic Acid


  • Enzyme Inhibitors
  • Nitric Oxide
  • Trinitrobenzenesulfonic Acid
  • Arginine
  • Peroxidase
  • Nitric Oxide Synthase
  • NG-Nitroarginine Methyl Ester