The inducible nitric oxide synthase inhibitor ONO-1714 blunts dextran sulfate sodium colitis in mice.
In mice with acute dextran sulfate sodium colitis, we examined the effect of inducible nitric oxide synthase inhibition by (1S,5S,6R,7R)-7chloro-3-amino-5methyl-2-azabicyclo[4.1.0]heptane hydrochloride (ONO-1714) on colonic biochemistry, injury, and inflammation. Colonic luminal nitrate and nitrite were measured by the Griess reaction; inducible nitric oxide synthase messenger RNA expression by reverse transcription-polymerase chain reaction; and nitrotyrosine by immunohistochemistry. Mice with colitis showed increases in nitrate and nitrite, inducible nitric oxide synthase messenger RNA, and numbers of cells staining for nitrotyrosine. Colonic inflammation was severe. ONO-1714 inhibited increases in nitrate and nitrite and numbers of nitrotyrosine-positive cells; injury and inflammation also were reduced. Dextran sulfate sodium-induced increases in thiobarbituric acid-reactive substances, a lipid peroxidation marker, were blunted by ONO-1714, which also inhibited increases in mucosal inflammatory cytokines. Nitric oxide produced by inducible nitric oxide synthase may contribute to colonic inflammation by nitrosation, oxidative damage, and enhanced inflammatory cytokines.
Naito
Y
Y
First Department of Medicine, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, 602-8566, Kamigyo-ku, Kyoto, Japan. ynaito@koto.kpu-m.ac.jp
Takagi
T
T
Ishikawa
T
T
Handa
O
O
Matsumoto
N
N
Yagi
N
N
Matsuyama
K
K
Yoshida
N
N
Yoshikawa
T
T
D000578:Amidines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D016264:Dextran Sulfate; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000494:pharmacology* / Q000627:therapeutic use; D007202:Indicators and Reagents; D008054:Lipid Peroxides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism
C407360:7-chloro-3-imino-5-methyl-2-azabicyclo(4.1.0)heptane; D000578:Amidines; D016207:Cytokines; D004791:Enzyme Inhibitors; D006454:Hemoglobins; D006574:Heterocyclic Compounds, 2-Ring; D007202:Indicators and Reagents; D008054:Lipid Peroxides; D012333:RNA, Messenger; D009569:Nitric Oxide; D016264:Dextran Sulfate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse