3. Twelve months studies on the chronic toxicity of captopril in rats

The chronic administration of captopril to Sprague-Dawley rats was performed under the barrier system by feeding ad libitum with mixed diet in various concentrations of captopril with 3 months recovery period. The number of animals was 180 female and 180 male including 5 groups of control, 30, 100, 300 and 900 mg/kg/day. The maximum nontoxic dose was estimated as about 30 mg/kg/day for male but a little more than this for female rats. Body weight increase was significantly reduced in male but for the first 3 months in female rats. No death was ascribed to the toxic effect of captopril. Polydipsia and polyuria in male, and the significant increase in values of BUN and inorganic phosphate in both sexes were observed. The reduction in erythrocyte count, values of hemoglobin and hematocrit, hemosiderosis in reticulum cells of the spleen and Kupffer cells in the liver and the increase of erythropoieses indicated hemolytic anemia. Heart weight reduced while kidney weight increased. Pathological examination revealed hypertrophia and hyperplasia of JG cells and thickening of walls of afferent arterioles with hyperplasia of vascular smooth muscle cells and increase of collagen fibers. Thickening of walls extended to walls of the interlobular arteries which remained after withdrawal of captopril for 3 months though JG granules attenuated. The age-related increases of incidences of proteinuria and myocardial fibrosis were attenuated dose-dependently which are probably due to hypotension induced by captopril.