title: Comparison of effects of nitric oxide synthase (NOS) inhibitors on plasma nitrite/nitrate levels and tissue NOS activity in septic organs.
abstract: An excessive production of nitric oxide (NO) by NO synthase (NOS) is considered to contribute to circulatory disturbance, tissue damage, and refractory hypotention, which are often observed in septic disorders. It is anticipated that a selective inducible NOS (iNOS) inhibitor with excellent pharmacokinetics may be potentially effective as a novel and potent therapeutic intervention in sepsis. We examined whether or not a selective iNOS inhibitor shows iNOS selectivity at the tissue level, when administered systemically. The effects of four NOS inhibitors on plasma nitrite/nitrate (NOx) and tissue NOS levels were compared in major organs (lungs, liver, heart, kidneys, and brain) 6 hr after the injection of E. coli lipopolysaccharide (LPS) into male Wistar-King rats. The rats treated with the three iNOS inhibitors (N-(3-(aminomethyl)benzyl)acetamidine (1400W), (1 S, 5 S, 6 R, 7 R )-2-aza-7-chloro-3-imino-5-methylbicyclo [4.1.0] heptane hydrochloride (ONO-1714), and aminoguanidine) administered 1 hr after LPS injection, showed dose-dependent decreases in plasma NOx levels and NOS activity in the lungs. The non-selective NOS inhibitor (N(G)-methyl-L-arginine (L-NMMA)) had an effect only at the maximum dose. The differences in in vitro iNOS selectivity among these drugs did not correlate with iNOS selectivity at the tissue level. The relationship between plasma NOx levels and NOS activity in the lungs showed a linear relationship with or without the NOS inhibitors. In conclusion, the iNOS selectivity of these drugs does not seem to differ at the tissue level. Plasma NOx levels may be a useful indicator of lung NOS activity.
authors.affiliation: Department of Emergency & Critical Care Medicine, School of Medicine, Fukuoka University, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Abe
authors.forename: Akira
authors.initials: A
authors.lastname: Murai
authors.forename: Naomi
authors.initials: N
authors.lastname: Shimizu
authors.forename: Iku
authors.initials: I
authors.lastname: Okamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Katsuragi
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004926:Escherichia coli; D008070:Lipopolysaccharides; D008168:Lung / Q000201:enzymology; D008297:Male; D009566:Nitrates / Q000097:blood*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood*; D051381:Rats; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D014781:Viscera / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat