title: O,O,S-trimethyl phosphorothioate increases Ca2+ independent nitric oxide synthase activity in the lung but decreases Ca2+/calmodulin dependent type in the cerebellum in Fischer 344 rats.
abstract: In the present study, we investigated the possible role of nitric oxide synthase in lung injury using female Fischer 344 rats as a model animal and O,O,S-trimethyl phosphorothioate as an example of lung toxicants. One form of nitric oxide synthase, Ca2+/calmodulin dependent type, decreased monotonously in a dose-dependent manner in the cerebellum. In contrast, O,O,S-trimethyl phosphorothioate increased activities of Ca2+ independent nitric oxide synthase in the lung in a dose-associated manner from 5 mg/kg to 15 mg/kg, but decreased at 30 mg/kg. Lung toxicity of O,O,S-trimethyl phosphorothioate, however, as judged both by functional impairments (PaCO2 and [HCO3-]) and histopathological changes, increased sharply at 30 mg/kg. We thus tested the hypothesis that a potent nitric oxide synthase inhibitor, NG-nitro-L-arginine-methyl ester, may modify lung injury induced by O,O,S-trimethyl phosphorothioate. Treatment with NG-nitro-L-arginine-methyl ester at 20 mg/kg/day aggravated lung injury induced by O,O,S-trimethyl phosphorothioate: Pulmonary oedema and bleeding occurred, leading to an increase in mortalities at 15 mg/kg of O,O,S-trimethyl phosphorothioate, at which level it did not induce such changes as when dosed alone. These findings indicate that nitric oxide synthase in the lung might play a protective role in lung injury.
authors.affiliation: Department of Anesthesiology, Akita University School of Medicine, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: K
authors.initials: K
authors.lastname: Ohtaka
authors.forename: M
authors.initials: M
authors.lastname: Suzuki
authors.forename: N
authors.initials: N
authors.lastname: Hamade
authors.forename: Y
authors.initials: Y
authors.lastname: Wada
authors.forename: A
authors.initials: A
authors.lastname: Koizumi
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001831:Body Temperature; D001835:Body Weight; D002118:Calcium / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase; D009929:Organ Size; D063086:Organothiophosphates / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D002148:Calmodulin-Binding Proteins; D063086:Organothiophosphates; C019123:O,O,S-trimethyl phosphorothioate; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester