The novel prodrug-converting-enzyme (CE) inhibitor perindopril (S9490-3) diacid was found to be as potent as ramipril (Hoe498) diacid and more potent than enalapril (MK421) diacid and captopril against rat plasma CE in vitro (IC50 values were 3 X 10(-9), 2 X 10(-9), 1 X 10(-8), and 6 X 10(-8) mol/L, respectively). Four-week oral treatment with perindopril (0.1, 1, 3, and 10 mg/kg/day) in spontaneously hypertensive rats (SHRSP) lowered blood pressure (BP) dose-dependently with a threshold dose of 0.1 mg/kg/day and normalization of BP following doses between 1-3 mg/kg/day. Plasma CE was inhibited, angiogensinogen lowered, plasma renin concentration (PRC) and angiotensin I (ANGI) increased, all dose-dependently. CE was also inhibited in kidney, aortic wall, heart, lung, hypophysis, and brain cortex. Upon drug withdrawal, the BP depressant effect outlasted the effects on the plasma renin-angiotensin system (RAS) by more than a week. Perindopril, ramipril (both 1 mg/kg/day), and enalapril (30 mg/kg/day) showed equal antihypertensive actions in SHRSP, although their effects on parameters of the RAS in plasma were different. Our data reveal perindopril to be a potent antihypertensive drug. The findings are consistent with the view that the antihypertensive actions of CE inhibitors cannot be directly related to inhibition of the RAS in the plasma. Local interference with the RAS in tissue appears to be an additional factor involved.