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.
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.
Yamazaki
Y
Y
Department of Anesthesiology, Akita University School of Medicine, Japan.
Ohtaka
K
K
Suzuki
M
M
Hamade
N
N
Wada
Y
Y
Koizumi
A
A
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
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