[One month studies on the subacute toxicity of captopril in rats]

Subacute toxicity of captopril by daily oral administration at dose levels of 10 mg/kg, 30 mg/kg, 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg for one month was studied in Sprague-Dawley rats. In the 2700 mg/kg group, 13 of 18 males and 17 of 18 females died with marked emaciation and abdominal distension. In the 900 mg/kg group, 1 of 18 males and 3 of 18 females died also during the administration period. In dead animals, a marked dilatation of gastrointestinal tract was noted showing multiple hemorrhagic erosions and/or ulcers in the glandular stomach. The remainder of these groups exhibited polydipsia and polyuria during the dosage period. In the 300 mg/kg and 100 mg/kg groups, all animals survived throughout the entire experimental period showing polydipsia and polyuria. In the 30 mg/kg and 10 mg/kg groups, all animals survived also throughout the entire dosage period without showing any toxic sign. Regarding plasma analysis, the BUN and creatinine concentration was significantly elevated in the group of 100 mg/kg or more. In the hematological examination, there was a decrease of erythrocyte counts, hemoglobin contents and hematocrit values in the group of 300 mg/kg or more. Pathological examinations revealed a marked thickening of the wall in afferent arterioles and interlobular arteries of the kidney in association with hypertrophy and hyperplasia of juxtaglomerular cells in 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg groups. In these groups, multiple hemorrhagic erosions with or without ulcer were also noted in the glandular stomach. In the spleen, a slight increase of extramedullary hematopoiesis and hemosiderosis was noted in the 100 mg/kg, 300 mg/kg, 900 mg/kg and 2700 mg/kg groups, in which an increase of erythropoietic elements was also noted in the bone marrow. From these results, the maximum nontoxic dose was estimated as about 30 mg/kg/day by oral administration of captopril in the rats.