Dose-effect relationship of perindopril 10, 14 and 20 mg assessed by urine and plasma AcSDKP levels in mildly sodium-depleted healthy volunteers

BackgroundWe describe a pharmacodynamic study of the dose-effect relationship of perindopril arginine at 10, 14, and 20 mg with in vivo angiotensin-converting enzyme (ACE) activity, assessed by urine and plasma AcSDKP levels, as well as the effect on plasma active renin concentrations and blood pressure.MethodsThis randomized, double-blind, four-period, crossover study involved single-dose administration of perindopril arginine (10, 14, and 20 mg or placebo) to 32 healthy male normotensive mildly sodium-depleted volunteers. Blood and urine were collected over 48 h for AcSDKP, ACE activity, and plasma active renin measurements.ResultsThere were dose-related increases in urinary AcSDKP excretion and plasma AcSDKP concentration after administration of perindopril, with significant between-period differences (estimate of the median difference in urinary excretion over 48 h of AcSDKP, 49.1 [95% CI: 15.3-82.0] nmol for 14 versus 10 mg, and 73.2 [95% CI: 44.9-106.3] nmol for 20 versus 14 mg). Consequently, a dose-dependent increase in plasma active renin concentration was observed. Even though each dose of perindopril 10 to 20 mg was associated with a significant 24-h ambulatory blood pressure reduction versus placebo, no dose-dependency was detected in these normotensive subjects.ConclusionsAdministration of perindopril arginine 10, 14, or 20 mg to mildly sodium-depleted healthy volunteers is associated with a dose-dependent inhibition of in vivo ACE activity with significant between-dose differences. This effect was associated with a dose-dependent increase in plasma active renin concentration, indicating a dose-dependent blockade of the renin angiotensin system.