Angiotensin AT 1 receptor inhibition, angiotensin-converting enzyme inhibition, and combination therapy with developing heart failure: Cellular mechanisms of action

Abstract

Background: Past studies have shown that angiotensin-converting enzyme inhibition (ACEI) alone, angiotensin AT 1 receptor blockade (AT 1 block) alone, and combined treatment have differential effects on left ventricular (LV) function and geometry with developing congestive heart failure (CHF). The purpose of this study was to more carefully examine the cellular basis for these differential effects by using a model of pacing CHF. Methods and Results: Pigs were randomly assigned to five groups: (1) rapid pacing (240 bpm) for 3 weeks (n = 9), (2) concomitant ACEI (benazeprilat, 0.187 mg/kg/day) and pacing (n = 9), (3) concomitant AT 1 block (valsartan, 3 mg/kg/day) and pacing (n = 9), (4) concomitant ACEI and AT 1 receptor blockade (benazeprilat/valsartan, 0.05/3 mg/kg/day, respectively) and pacing (n = 9), and (5) sham controls (n = 10). The dosage protocol was based on obtaining a 50% reduction in angiotensin I and angiotensin II pressor response with no significant effects on mean basal arterial pressure. In the pacing group, LV fractional shortening (LVFS) fell compared with control group (13.4 ± 1.4 v 39.1 ± 1.0%, P < .05). With AT 1 block, LVFS was unchanged from pacing only. ACEI and combined treatment increased LVFS from pacing values (25.2 ± 0.9 v 20.9 ± 1.9%, respectively, P < .05). LV myocyte shortening velocity was reduced with chronic pacing compared with control group (27.2 ± 0.6 v 58.6 ± 1.2 μm/s, P < .05) and remained reduced with AT 1 block (28.0 ± 0.5 μm/s, P < .05). Myocyte shortening velocity increased with ACEI or combination treatment (36.9 ± 0.7 ± 0.7 v 42.3 ± 0.8 μm/s, respectively, P < .05). Concomitant treatment with either ACEI or AT 1 blockade normalized myocyte action potential duration. In the combined ACEI and AT 1 blockade group, all parameters of the myocyte action potential were unchanged from control values. Conclusions: This study showed that combined ACEI and AT 1 receptor blockade produced beneficial effects on myocyte contractility and electrophysiology when compared with either monotherapy alone and therefore may provide unique benefits with CHF.