ADDITIVE EFFECTS OF COMBINED ANGIOTENSIN-CONVERTING ENZYME-INHIBITIONAND ANGIOTENSIN-II ANTAGONISM ON BLOOD-PRESSURE AND RENIN RELEASE IN SODIUM-DEPLETED NORMOTENSIVES

Background Angiotensin-converting enzyme (ACE) inhibi tors do not decr ease plasma angiotensin (Ang) II levels 24 hours after drug intake to the same extent as at peak. This intermittent partial ''escape'' is ex plained either by a renin-mediated reactive rise in plasma Ang I or by non-ACE-dependent Ang II generation. We therefore tested the hypothes is that a combination of ACE inhibition and Ang II blockade may have a dditive biological and hemodynamic effects. Methods and Results In a s ingle-dose, double-blind, randomized, four-way, crossover study, an An g 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. Whe n captopril 50 mg and losartan 50 mg were given alone, the magnitude o f their effects on blood pressure, plasma active renin, Ang I, and ald osterone was similar, whereas the kinetics of their effects were diffe rent, reflecting differences in drug pharmacokinetics. The losartan-ca ptopril combination completely suppressed the rise in plasma Ang II in duced 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, th e losartan-captopril combination induced a significantly greater decre ase in mean blood pressure than that produced by either losartan or ca ptopril alone (73+/-7 mm Hg versus 79+/-8 mm Hg versus 81+/-7 mm Hg, r espectively, P<.05). The maximum placebo-subtracted falls in mean bloo d pressure for the losartan-captopril combination, captopril 50 mg, an d losartan 50 mg were 14+/-5 mm Hg, 10+/-3 mm Hg, and 9+/-6 mm Hg, res pectively (F2.22=3.45, P<.05). The duration of the mean blood pressure fall was not prolonged by the combination. After combined losartan-ca ptopril administration, the area under the plasma active renin versus time curve (0 to 24 hours) was significantly increased when compared w ith either losartan or captopril alone (6404+/-2961 pg . h . mL(-1) ve rsus 3105+/-1461 pg . h . mL(-1) versus 2092+/-867 pg . h . mL(-1), re spectively, P<.05). The combination had no additive effects on plasma aldosterone decrease when compared with either losartan or captopril a lone (58+/-17% versus 51+/-20% versus 53+/-21%, respectively, NS). Con clusions The combined administration of a standard single oral dose of an ACE inhibitor and an Ang II antagonist to mildly sodium-depleted n ormal 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.