4. THREE MONTHS SUBACUTE TOXICITY OF CAPTOPRIL IN BEAGLE DOGS

Abstract

Thirty four beagle dogs, male and female were orally given 10, 30, 100 and 200mg/kg/day of captopril, an angiotensin converting enzyme inhibitor, for 3 months followed by a recovery test for 4 weeks. One of 4 female dogs which were treated with the highest dose of 200mg/kg/day throughout the experimental period died of bronchial pneumonia. Hypersalivation and occasionally vomiting was observed in dogs treated with 100 and 200mg/kg/day. Skin eruption such as erythema and papules was observed mostly at the ventral surface of the neck, chest and upper abdomen in dogs in these two experimental groups. Histological examination of the lesion revealed cellular infiltration with edema and expansion in the dermis and slight hyperkeratosis with parakeratosis and acanthosis. Changes. in erythrocyte counts, hematocrit values and hemoglobin contents during the course of administration were variable among dogs but these were more obvious in animals treated with higher doses. An increase in erythropoiesis of the bone marrow, extramedullary hematopoiesis and slight hemosiderosis in liver and spleen were revealed by histological examination. Above histological observations suggest that captopril may cause hemolysis. Hypertrophy and hyperplasia of juxtaglomeruiar cells with increased number of JG granules were shown in the highest dosage group even 4 weeks after suspension of captopril administration. A distinct plasma renin activity supported the morphological changes. From the results of three months administration of captopril to beagle dogs, the maximum non-toxic dose may be around 10 mg/kg/day and toxic dose 100 mg/kg/day.