Cardioprotective and survival benefits of long-term combined therapy with β2 adrenoreceptor (AR) agonist and β1 AR blocker in dilated cardiomyopathy postmyocardial infarction

We have reported therapeutic effectiveness of pharmacological stimulation of beta(2) adrenoreceptors (ARs) to attenuate the cardiac remodeling and myocardial infarction (MI) expansion in a rat model of dilated cardiomyopathy (DCM) post-MI. Furthermore, the combination of beta(2) AR stimulation with beta(1) AR blockade exceeded the therapeutic effectiveness of beta(1) AR blockade. However, these studies were relatively short ( 6 weeks). In this study, in the same experimental model, we compared different effects, including survival benefit, of combined therapy with the beta(1) AR blocker, metoprolol, plus the beta(2) AR agonist, fenoterol (beta(-)(1)beta(+)(2)), and either therapy alone ( beta(-)(1) or beta(+)(2)) during the 1-year study. Therapy was started 2 weeks after permanent ligation of the left coronary artery. Cardiac remodeling, MI expansion, and left ventricular function were assessed by serial echocardiography and compared with untreated animals (nT). Sixty-seven percent mortality in nT was reduced to 33% in the beta(-)(1) beta(2)+ ( p < 0.01). Progressive cardiac remodeling observed in nT and beta(-)(1) was significantly attenuated in beta(-)(1) beta(+)(2) during the first 6 months of treatment. In beta(-)(1) beta(+)(2), MI expansion was completely prevented, and functional decline was significantly attenuated during the entire year. Myocardial apoptosis was significantly reduced in both beta(-)(1)beta(+)(2) and beta(-)(1). A reduction of cardiac beta(1) AR density and decreases in chronotropic and contractile responses to beta(2) AR-specific stimulation in the absence of a reduction of beta 2 AR density in nT were precluded in rats receiving combined therapy. The results demonstrate the cardioprotective and survival benefit of long-term combination therapy of beta(2) AR agonists and beta(1) AR blockers in a model of DCM.