O,O,S-TRIMETHYL PHOSPHOROTHIOATE INCREASES CA2-OXIDE SYNTHASE ACTIVITY IN THE LUNG BUT DECREASES CA2+( INDEPENDENT NITRIC)CALMODULIN DEPENDENT TYPE IN THE CEREBELLUM IN FISCHER-344 RATS/

In the present study, we investigated the possible role of nitric oxid e synthase in lung injury using female Fischer 344 rats as a model ani mal and O,O,S-trimethyl phosphorothioate as an example of lung toxican ts. 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-associate d manner from 5 mg/kg to 15 mg/kg, but decreased at 30 mg/kg. Lung tox icity of O,O,S-trimethyl phosphorothioate, however, as judged both by functional impairments (PaCO2 and [HCO3-]) and histopathological chang es, increased sharply at 30 mg/kg. We thus tested the hypothesis that a potent nitric oxide synthase inhibitor, N-G-nitro-1-arginine-methyl ester, may modify lung injury induced by O,O,S-trimethyl phosphorothio ate. Treatment with N-G-nitro-1-arginine-methyl ester at 20 mg/kg/day aggravated lung injury induced by O,O,S-trimethyl phosphorothioate: Pu lmonary oedema and bleeding occurred, leading to an increase in mortal ities 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 ind icate that nitric oxide synthase in the lung might play a protective r ole in lung injury.