Role of endogenous nitric oxide (NO) and NO synthases in healing of indomethacin-induced intestinal ulcers in rats.
We examined the roles of nitric oxide (NO) and NO synthase (NOS) isozymes in the healing of indomethacin-induced small intestinal ulcers in rats. Animals were given indomethacin (10 mg/kg, s.c.) and killed 1, 4 and 7 days after the administration. Indomethacin (2 mg/kg), N(G)-nitro-L-arginine methyl ester (L-NAME: a nonselective NOS inhibitor: 10 mg/kg) and aminoguanine (a relatively selective iNOS inhibitor: 20 mg/kg) were given s.c. once daily for 6 days, the first 3 days or the last 3 days during a 7-day experimental period. Both indomethacin and L-NAME significantly impaired healing of these lesions, irrespective of whether they were given for 6 days, first 3 days or last 3 days. The healing was also impaired by aminoguanine given for the first 3 days but not for the last 3 days. Expression of iNOS mRNA in the intestine was up-regulated after ulceration, persisting for 2 days thereafter, and the Ca(2+)-independent iNOS activity also markedly increased with a peak response during 1-2 days after ulceration. Vascular content in the ulcerated mucosa as measured by carmine incorporation was decreased when the healing was impaired by indomethacin and L-NAME given for either the first or last 3 days as well as aminoguanidine given for the first 3 days. These results suggest that endogenous NO plays a role in healing of intestinal lesions, in addition to prostaglandins, yet the NOS isozyme mainly responsible for NO production differs depending on the stage of healing: iNOS in the early stage and cNOS in the late stage.
Takeuchi
Koji
K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, 607-8414, Japan. takeuchi@mb.kyoto-phu.ac.jp
Hatazawa
Ryo
R
Tanigami
Mayu
M
Tanaka
Akiko
A
Ohno
Ryoko
R
Yokota
Aya
A
D000818:Animals; D004195:Disease Models, Animal; D004381:Duodenal Ulcer / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D007213:Indomethacin / Q000009:adverse effects; D007279:Injections, Subcutaneous; D007421:Intestine, Small / Q000098:blood supply; D007527:Isoenzymes; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D006146:Guanidines; D007527:Isoenzymes; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin