Effects of chronic nitric oxide synthase inhibition on TNB-induced colitis in rats.
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.
Pfeiffer
C J
CJ
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg 24061-0442, USA.
Qiu
B S
BS
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015918:Infusion Pumps, Implantable; D007279:Injections, Subcutaneous; D007413:Intestinal Mucosa / Q000201:enzymology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014302:Trinitrobenzenesulfonic Acid
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D014302:Trinitrobenzenesulfonic Acid; D001120:Arginine; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester