Abstract
SA446 [(2R, 4R)-2-(o-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxylic acid] (30 mg/kg/day), an orally active angiotensin-converting enzyme inhibitor, lowered significantly indirect systolic blood pressure (SBP) of 2-kidney, 1-clip renal hypertensive rats (RHR) by consecutive oral administration over a 14 week period. Daily oral dosing of hydralazine (2 mg/kg/day) for 14 weeks had little or no effect on SBP, but potentiated the antihypertensive effect of SA446. One to two weeks after discontinuation of the drugs, SBP in SA446 and the combination groups returned to the control level. Survival rates were 64%, 30% in the control and hydralazine group, respectively, but no death was observed in the SA446 group and the combination group throughout the administration period. Twenty-four hour urine volume and water intake tended to increase in the hydralazine group through the administration period, but increased apparently in the SA446 group and the combination group after discontinuation of the drugs. Daily oral dosing of SA446 (45 mg/kg/day) for over 16 weeks completely prevented the development of hypertension in spontaneously hypertensive rats (SHR). Daily oral dosing of hydralazine (2 mg/kg/day) similarly prevented the development. The combined effect with SA446 and hydralazine on the development was also observed. SBP in the SA446 group and the combination group increased gradually after discontinuation of the drugs, but were maintained at a low level as compared with the control group 3 weeks after discontinuation, while hydralazine gave a rapid return. No influences were observed in 24 hr-urine volume and water intake during and after the administration period in SHR. These results demonstrate that long-term treatment with SA446 could maintain the antihypertensive effect in RHR and prevent the development of hypertension in SHR and that the combined effect with SA446 and hydralazine was also observed on the antihypertensive effects.
