Dual action of nitric oxide in the pathogenesis of ischemia/reperfusion-induced mucosal injury in mouse stomach.
OBJECTIVE
We investigated the roles of NO/NOS isoforms in the pathogenesis of ischemia/reperfusion (I/R)-induced gastric injury in mouse stomachs.


METHODS
Under urethane anesthesia, the celiac artery was clamped, and then reperfusion was established 30 min later by removal of the clamp. After a 60-min reperfusion, the stomach was examined for macroscopic lesions.


RESULTS
Following I/R, hemorrhagic lesions were generated in the mucosa, although ischemia alone caused no visible damage. Prior administration of L-NAME (a nonselective NOS inhibitor) significantly aggravated these lesions, in a L-arginine-inhibitable manner. By contrast, the selective iNOS inhibitor 1400W significantly prevented the occurrence of I/R-induced gastric lesions. The mucosal MPO activity was increased after I/R, and this response was enhanced and attenuated by prior administration of L-NAME and 1400W, respectively. Interestingly, the later treatment with L-NAME, given 10 min before reperfusion, significantly reduced the severity of the I/R-induced gastric damage, in a L-arginine-dependent manner. The expression of iNOS mRNA was up-regulated in the stomach following I/R, with an increase of mucosal NO content, and the NO production was significantly inhibited by both L-NAME and 1400W.


CONCLUSIONS
Endogenous NO plays a dual role in the pathogenesis of IR-induced gastric damage; NO/cNOS is protective while NO/iNOS is proulcerogenic during I/R.
Kobata
Atsushi
A
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan.
Kotani
Tohru
T
Komatsu
Yoshino
Y
Amagase
Kikuko
K
Kato
Shinichi
S
Takeuchi
Koji
K
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000201:enzymology / Q000473:pathology; D007097:Imines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D013276:Stomach Ulcer / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D007097:Imines; C496401:N-((3-(aminomethyl)phenyl)methyl)ethanimidamide; D009569:Nitric Oxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester