|Budget Amount *help
¥3,200,000 (Direct Cost : ¥3,200,000)
Fiscal Year 1999 : ¥1,000,000 (Direct Cost : ¥1,000,000)
Fiscal Year 1998 : ¥2,200,000 (Direct Cost : ¥2,200,000)
Previously, in order to study the pathogenesis of traumatic DIC, we investigated and confirmed the onset of DIC following hemorrhagic invasion in the rat, and at that time we noticed a rapid increase in nitric oxide (NO) in the tissue in the early stage after the invasion. It was suggested that the increase in NO production would serve as an indication for diagnosis of traumatic DIC. In this study, we investigated the time course and mechanism of NO production in the tissue and its histopathology following hemorragic invasion in the rat, in comparsion with the rat following endotoxin administration. Then we investigated therapeutic effects of NO synthase (NOS) inhibitors for these morbid states.
In the fiscal year 1998, the time course of NO production in the tissue following hemorrhagic invasion (bleeding of 30% of predetermined total blood volume) in the rat was recorded with an NO-selective electrode(φ200μm, Intermedical Co.) set in the kidney tissue, comparing with that rat followin
g endotoxin administration (LPS, E, coli, 10mg/kg iv). In the hemorrhagic invasion, increase in NO production in the early stage was observed and it was suggested strongly to be due to constitutive NOS (cNOS) by the investigation with NOS inhibitors. On the contrary, in the endotoxin administration NO production was not observed at all in the early stage, but it begun to increase gradually 2〜3hr after the administration and reached a peak after 4〜6hr, and it was suggested strongly to be due to inducible NOS (iNOS). We could detect a characteristic ESR signal of NO in the sample solution of the kidney tissue following both the invasions.
In the fiscal year 1999, therapeutic effects of NOS inhibitors and other drugs for these morbid states were investigated. NOS inhibitors have been tried to treat for various types of circulatory shock. In this experiment NOS inhibitors reduced partly the changes in the coagulation-fibrinolytic system and plasma cytokine levels induced by the invasions, but did not ameliorate significantly histopathological changes. On the other hand, antithrombin III ameliorated changes in coagulation-fibrinolytic system and plasma cytokine levels, and also histopathological changes, too. Theraputic effects of NOS inhibitors for these morbid states should be further investigated in detail on types, dosages, time of treatment of NOS inhibitors, considering two sided roles of NO effect. Less