各種高血圧ラットに対する変換酵素抑制剤Captoprilの長期経口投与による降圧効果の比較検討

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Captopril, a potent and orally active converting enzyme inhibitor is believed to exert its hypotensive effect largely through the inhibition of the renin-angiotensin system (RAS). In order to examine the renin dependency of blood pressure (BP) in normal rats and rats with two-kidney Goldblatt hypertension (2KGH), spontaneous hypertension (SH) and DOCA-salt hypertension (DSH), we examined the responses of these animals to prolonged administration of captopril. Two types of studies were done on the hypertensive animals : one was performed in the chronic phase when hypertension was established (chronic phase study), and the other was started in the prehypertensive phase (prevention study). Normal rats were studied with and without captopril treatment. 2KGH rats and SHR in the chronic phase study had no untreated controls and the significances of differences were examined between the BP of the control period and those of the treatment period. In other studies each model had its untreated controls. Each experiment consisted of control, treatment, and recovery periods. Captopril, dissolved in the drinking water at a concentration of 0.5 mg/ml, was given during the treatment period to all animals except the untreated controls. The diet contained 1.3% NaCl by weight. BP, water intake, consumption of captopril, urine volume and the urinary excretion of electrolytes were measured in the normal rats and in the hypertensive rats in the chronic phase study. BP, water intake, and the consumption of captopril were measured in the prevention study. BP was measured using a plethysmographic tail method without anesthesia. Normal rats consumed a mean of 85 mg/kg/day of captopril and BP fell from a mean control value of 112 ± 2 mmHg (Mean ± SE) to 99 ± 3 mmHg on the second day of the treatment period and remained at about this level thereafter; however, a significant difference of the BP from that of the untreated controls was noted only on the sixth day of the treatment period (p <0.001). Chronic 2KGH rats consumed a mean of 70 mg/kg/day of captopril 5 months after renal artery constriction and BP decreased progressively from 181 ± 8 mmHg on the last day of the control period to a minimum of 130 ± 5 mmHg on the ninth day of treatment (p < 0.001). While there were considerable fluctuations in BP during the treatment period, it remained substantially less than that of the control period. By the twelfth day of the recovery period the BP had returned to values approximating those of the control period. In the prevention study with 2KGH, captopril was started one day after the constriction of the left renal artery and continued for 20 days. Captopril prevented the development of hypertension during the treatment period. By the fifteenth day of the recovery period there was no significant difference between the BP of these rats and those of their control group. Established SHR (12 weeks of age) also had a steep fall in BP when they consumed a mean of 67 mg/kg/day of captopril. While their BP fell significantly, it did not reach normotensive levels. The expected BP rise in young SHR (5 weeks of age) was prevented by their consumption of a mean of 68 mg/kg/day of captopril. The significant difference between the BP of these rats and those of their untreated controls disappeared on the seventh day of the recovery period. Chronic DSH rats had no BP reduction with captopril. DSH was not prevented by captopril even though mean consumption of captopril by these rats was more than 200 mg/ kg/day. No natriuretic, kaliuretic or diuretic activity of captopril was found in this study. Both chronic 2KGH and SHR, as well as normal rats had depressor responses to captopril even though sodium intake was not restricted.
日本内分泌学会の論文

各種高血圧ラットに対する変換酵素抑制剤Captoprilの長期経口投与による降圧効果の比較検討

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