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.

Changes in Nitric Oxide Synthase Activities in the Cerebellum during Development and Aging of C57BL/6 Mice.

“…Non-enzymatic conversion of arginine to citrulline was determined by the assay mixture of which enzyme source was replaced by water at least three samples independently in each experiment. We confirmed that those values of enzyme activities were proportional up to 60,ug protein amounts (Yamazaki et al 1994). …”

S-Methylation of O,O-Dialkyl Phosphorodithioic Acids: O,O,S-Trimethyl Phosphorodithioate and Phosphorothiolate as Metabolites of Dimethoate in Mice

“…(MeO) 2 P(S)SMe and (MeO) 2 P(O)SMe are poor inhibitors of cholinesterase (4, 5) and poor alkylating agents (23,24). Several studies have focused on the lung as a primary site of toxicity for (MeO) 2 P(O)SMe (7,8,(25)(26)(27). (MeO) 2 P(S)SMe is not a lung-specific toxin, and when administered to rats in small amounts, it prevents the lung damage caused by analogs of (MeO) 2 P(O)SMe (8,28).…”