Effects of ACE inhibitor, AT(1) antagonist, and combined treatment in micewith heart failure

We tested the hypothesis that a combination of angiotensin-converting enzym e 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 bra dykinin. During treatment with AT, ant, increased angiotensin II could acti vate AT, receptors, with an antitrophic effect. To test this hypothesis, we used a mouse model of HF induced by myocardial infarction. Seven days afte r 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 e ach). Cardiac function was evaluated in conscious mice during the treatment period. The HF-vehicle group showed significantly decreased left ventricul ar (LV) ejection fraction (EF), shortening fraction (SF), and cardiac outpu t (CO) and increased LV dimensions, interstitial collagen, and myocyte cros s-sectional area (MCSA) compared with controls. Treatment with ACEi or AT(1 )-ant significantly increased EF, SF, and CO and decreased LV dimensions an d MCSA in mice with HF. However, a combination of these drugs did not impro ve cardiac function more than ACEi or AT(1)-ant alone. We concluded that AC Ei and AT(1)-ant have similar cardioprotective effects and may reach maxima l effect when given individually; thus no further improvement can be achiev ed with combined therapy in mice with HF.