Effects of ACE inhibitor, AT1 antagonist, and combined treatment in mice with heart failure

We tested the hypothesis that a combination of angiotensin-converting enzyme inhibitor (ACEi) and angiotensin II type 1 receptor antagonist (AT(1)-ant) may have an additive cardioprotective effect in mice with heart failure (HF), because these two agents could have other mechanisms of action besides interrupting the renin-angiotensin system. ACEi prevent degradation of bradykinin. During treatment with AT, ant, increased angiotensin II could activate AT, receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days after surgery, mice were divided into six groups and treated for 23 weeks: (a) sham ligation; (b) HF-vehicle; (c) HF-ACEI; (d) HF-AT(1)-ant; (e) HF-ACEi + AT(1)-ant (half dose of each); and (f) HF-ACEi + AT(1)-ant (full dose of each). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricular (LV) ejection fraction (EF), shortening fraction (SF), and cardiac output (CO) and increased LV dimensions, interstitial collagen, and myocyte cross-sectional area (MCSA) compared with controls. Treatment with ACEi or AT(1)-ant significantly increased EF, SF, and CO and decreased LV dimensions and MCSA in mice with HF. However, a combination of these drugs did not improve cardiac function more than ACEi or AT(1)-ant alone. We concluded that ACEi and AT(1)-ant have similar cardioprotective effects and may reach maximal effect when given individually; thus no further improvement can be achieved with combined therapy in mice with HF.