Aminonucleosideネフローゼラットにおける選択的Thromboxane A2合成酵素阻害剤OKY‐046の尿蛋白抑制効果について

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  • Effects of a selective thromboxane A2 synthetase inhibitor, OKY-046, on proteinuria of aminonucleoside nephrotic rats.

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The effect of a selective Thromboxane A2 (TXA2) synthetase inhibitor, OKY-046, on reducing proteinuria was evaluated in the nephrotic rats. Protein excretion, and the contents of creatinine and arachidonic acid metabolites (6-keto-Prostaglandin F and Thromboxane B2, a stable metabolite of TXA2) in urine were measured, and the synthesis of above compounds were also measured by biochemical assays using isolated nephrotic rat's kidneys. The preparation of nephrotic rats and the effect of OKY-046 on nephrotic rats were done as follows: male Wister rats were administrated daily subcutaneous injections of Aminonucleoside (7 mg/kg/day for 5 days and 10 mg/kg/day for 10 days), the effect of OKY-046 was observed by oral administration at 50 mg/kg/day, twice a day. Oral administration of OKY-046 decreased protein excretion in urine at the early stage of the disease. But at the developed stage, OKY-046 had no significant effects. Whereas Thromboxane B3 excretion in urine was significantly inhibited during the all stage. On biochemical assays using nephrotic rats in the presence of OKY-046, Thromboxane B2 synthesis was significantly inhibited as observed in in vivo assays, and furthermore inhibition rate of Thromboxane B2 in cortex was higher than that in medulla. We suggest that excessive synthesis of Thromboxane A2 in the hidney causes subsequent proteinuria at the early stage, and OKY-046 is effective on decreasing protein excretion in urine, but at the developed phase it can't decrease proteinuria no longer, probably many chemical-mediated factors except for Thromboxane A2 and/or destructive lesions of the kidney would take part in proteinuria.

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