Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives

Abstract

Background: Angiotensin-converting enzyme (ACE) inhibitors do not decrease plasma angiotensin (Ang) II levels 24 hours after drug intake to the same extent as at peak. This intermittent partial "escape" is explained either by a renin-mediated reactive rise in plasma Ang I or by non-ACE-dependent Ang II generation. We therefore tested the hypothesis that a combination of ACE inhibition and Ang II blockade may have additive biological and hemodynamic effects.

Methods and results: In a single-dose, double-blind, randomized, four-way, crossover study, an Ang II antagonist (losartan 50 mg), an ACE inhibitor (captopril 50 mg), their combination, and matched placebos were orally administered to 12 normotensive male volunteers maintained in mild sodium depletion. When captopril 50 mg and losartan 50 mg were given alone, the magnitude of their effects on blood pressure, plasma active renin, Ang I, and aldosterone was similar, whereas the kinetics of their effects were different, reflecting differences in drug pharmacokinetics. The losartan-captopril combination completely suppressed the rise in plasma Ang II induced by losartan 2 hours after drug intake (3.3 +/- 3.6 pg/mL versus 20.3 +/- 19.1 pg/mL, respectively, P < .05). Six hours after drug intake, the losartan-captopril combination induced a significantly greater decrease in mean blood pressure than that produced by either losartan or captopril alone (73 +/- 7 mm Hg versus 79 +/- 8 mm Hg versus 81 +/- 7 mm Hg, respectively, P < .05). The maximum placebo-subtracted falls in mean blood pressure for the losartan-captopril combination, captopril 50 mg, and losartan 50 mg were 14 +/- 5 mm Hg, 10 +/- 3 mm Hg, and 9 +/- 6 mm Hg, respectively (F2.22 = 3.45, P < .05). The duration of the mean blood pressure fall was not prolonged by the combination. After combined losartan-captopril administration, the area under the plasma active renin versus time curve (0 to 24 hours) was significantly increased when compared with either losartan or captopril alone (6404 +/- 2961 pg.h.mL-1 versus 3105 +/- 1461 pg.h.mL-1 versus 2092 +/- 867 pg.h.mL-1, respectively, P < .05). The combination had no additive effects on plasma aldosterone decrease when compared with either losartan or captopril alone (58 +/- 17% versus 51 +/- 20% versus 53 +/- 21%, respectively, NS).

Conclusions: The combined administration of a standard single oral dose of an ACE inhibitor and an Ang II antagonist to mildly sodium-depleted normal subjects (1) had a major additive effect on plasma renin rise, (2) induced an additional mean blood pressure reduction, and (3) had no additive effect on plasma aldosterone fall.