Therapeutic Efficacy of a Combination of a β1-Adrenoreceptor (AR) Blocker and β2-AR Agonist in a Rat Model of Postmyocardial Infarction Dilated Heart Failure Exceeds That of a β1-AR Blocker plus Angiotensin-Converting Enzyme Inhibitor

We had proposed previously a novel combination of beta 2-adrenoreceptor (AR) agonist and beta 1-AR blocker that in the rat model of postmyocardial infarction (MI) dilated cardiomyopathy exceeds the therapeutic effectiveness of either monotherapy. In the present study, we compared that treatment with a combination of beta 1-AR blocker and angiotensin-converting enzyme inhibitor (ACEi), a current standard chronic heart failure (CHF) therapy. Two weeks after coronary artery ligation, rats were divided into groups of similar average MI size, measured by echocardiography, and the following 12-month treatments were initiated: fenoterol (250 mu g/kg/day), a beta 2-AR agonist, plus metoprolol (100 mg/kg/day), a beta 1-AR blocker (beta 1-beta 2+); metoprolol plus enalapril (20 mg/kg/day), an ACEi (beta 1-ACEi); and a combination of all three drugs (beta 1-beta 2+ACEi). These treatment groups were compared with each other and with nontreated (nT) and sham groups. The 12-month mortality was significantly reduced in all treatment groups (44% in beta 1-beta 2+, 56% in beta 1-beta 2+ACEi, 59% in beta 1-ACEi versus 81% in nT). Bimonthly echocardiography revealed significant attenuation of the left ventricular (LV) chamber remodeling, LV functional deterioration, and MI expansion in all three treatment groups, but effects were significantly more pronounced when treatment included a beta 2-AR agonist. The results indicated that a combination of beta 1-AR blocker and beta 2-AR agonist is equipotent to a combination of beta 1-AR blocker and ACEi in the treatment of CHF in rats, with the respect to mortality, and exceeds the latter with respect to cardiac remodeling and MI expansion. Thus, this novel therapeutic regimen for CHF warrants detailed clinical investigation.