Protection by constitutively formed nitric oxide of intestinal damage induced by indomethacin in rats.
In the present study, we investigated a protective role of constitutively occurred nitric oxide (NO) against indomethacin-induced intestinal lesions in rats. Indomethacin (10 mg/kg) was given s.c. to animals without fasting, and the intestinal mucosa was examined for lesions 24 h later. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) was given s.c. 0.5 h before or 6 hr after indomethacin, while the NO donor (+/-)-(E)-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexnamine (NOR-3) was given s.c. 0.5 h before indomethacin. Indomethacin caused hemorrhagic lesions in the small intestine, accompanied with an increase in intestinal motility and bacterial translocation. These lesions were markedly prevented or worsened, respectively, by later or prior administration of L-NAME (20 mg/kg), in a L-arginine-sensitive manner. The worsening effect of L-NAME (5-20 mg/kg) on these lesions was dose-dependently observed in association with further enhancement of the bacterial translocation and intestinal hypermotility following indomethacin. By contrast, prior administration of NOR-3 (1-6 mg/kg) dose-dependently prevented the development of intestinal lesions, together with suppression of the bacterial translocation and intestinal hypermotility in response to indomethacin. On the other hand, both indomethacin and L-NAME decreased intestinal mucus and fluid (water) secretion in the small intestine, while NOR-3 increased these secretions. These results suggest that (1) NO occurred constitutively exerts a protective action against indomethacin-induced intestinal ulceration, and (2) this effect is related with prevention of bacterial translocation, the process functionally associated with increase of mucus and fluid secretions as well as inhibition of intestinal hypermotility.
Tanaka
A
A
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan.
Mizoguchi
H
H
Kunikata
T
T
Miyazawa
T
T
Takeuchi
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D018988:Bacterial Translocation / Q000187:drug effects; D001826:Body Fluids / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009093:Mucus / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D010437:Peptic Ulcer / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009569:Nitric Oxide; C061872:FK 409; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin