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.
The purpose of this study was to investigate the roles of lipid peroxidation and a prototypical radical generating enzyme, xanthine oxidase, in lung injury caused by O,O,S-trimethyl phosphorothioate (OOS-TMP). Animals (five per group) were dosed with OOS-TMP at 40 mg/kg and sacrificed on the 1st, 3rd or 7th day after treatment. OOS-TMP increased lipid peroxidation (Mean +/- S.E.) to 139 +/- 9.6% of the control values in the lung and to 623 +/- 203% in the liver on the 1st day. When rats were dosed with OOS-TMP at 20, 40 and 60 mg/kg, lipid peroxidation in the lung and the liver were increased in a dose-dependent manner. In the lung, the total activity of xanthine oxidase was coincidentally increased. In contrast, the activities of superoxide dismutase and catalase were not affected. Effects of OOS-TMP on lipid peroxidation and the total activity of xanthine oxidase were completely abolished by coadministration with O,O,O-trimethyl phosphorothionate of a non-toxic dose (1 mg/kg), which antagonizes the lung injury after treatment with OOS-TMP. The present results indicate that free radical formation may be involved in lung injury after OOS-TMP treatment through activation of radical producing enzymes such as xanthine oxidase.
To evaluate the changes in right ventricular function during controlled mechanical ventilation (CMV) without positive end-expiratory pressure (PEEP) and during spontaneous breathing, we compared right ventricular ejection fraction (RVEF), right ventricular end-diastolic volume index (RVEDVI), and right ventricular end-systolic volume index (RVEDVI) using a thermodilution technique after coronary artery bypass graft surgery. Patients were divided into two groups on the basis of changes in RVEDVI from CMV to spontaneous breathing: group U (n = 6) consisted of patients whose RVEDVI increased during spontaneous breathing compared with mechanical ventilation, group D (n = 3) consisted of patients whose RVEDVI decreased during spontaneous breathing compared with mechanical ventilation. PVRI values during CMV in group D were significantly larger than those in group U. Patients in group U showed no increase in RVEDVI, or decrease in RVEF during CMV without PEEP. However, the remaining 3 patients in group D showed an increase in RVEDVI and a decrease in RVEF during CMV. Mean PAP, RAP, RV systolic pressure, RV end-diastolic pressure, PWP, HR, and mean arterial pressure in both groups were comparable, and showed no significant difference at each of the measured points by 24 hrs postoperatively. Then, RVEF, RVEDVI and RVESVI measured by thermodilution technique is useful in evaluating ventricular function at bedside in ICU.
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