Therapeutic efficacy of a combination of a beta1-adrenoreceptor (AR) blocker and beta2-AR agonist in a rat model of postmyocardial infarction dilated heart failure exceeds that of a beta1-AR blocker plus angiotensin-converting enzyme inhibitor

Abstract

We had proposed previously a novel combination of beta2-adrenoreceptor (AR) agonist and beta1-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 beta1-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 microg/kg/day), a beta2-AR agonist, plus metoprolol (100 mg/kg/day), a beta1-AR blocker (beta1-beta2+); metoprolol plus enalapril (20 mg/kg/day), an ACEi (beta1-ACEi); and a combination of all three drugs (beta1-beta2+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 beta1-beta2+, 56% in beta1-beta2+ACEi, 59% in beta1-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 beta2-AR agonist. The results indicated that a combination of beta1-AR blocker and beta2-AR agonist is equipotent to a combination of beta1-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.

Fig. 1.

Kaplan-Meier survival curves after induction of MI in a sham-operated group, an untreated group, and three different treatment groups. The number of animals at the beginning of treatment was as follows: SH, 10; and nT, β1-ACEi, β1-β2+, and β1-β2+ACEi, 27 in each.

Fig. 2.

Average MI size in untreated and treated rats estimated by monthly Echo (left) or on the basis of histological measurements (right) and presented as percentage of LV. Top, all animals; bottom, animals that survived 12 months after the MI induction. ∗∗∗, p < 0.001 versus nT; †††, p < 0.001 versus β1-ACEi (pairwise comparison, group × time interaction with Bonferroni’s correction).

Fig. 3.

LV end-diastolic volume (left), end-systolic volume (middle), and ejection fraction (right) in untreated and treated rats estimated by bimonthly Echo during 12 months after induction of MI. Top, all animals; bottom, only animals that survived 12 months after induction of MI. ∗∗, p < 0.002 versus nT; †, p < 0.05 versus β1-ACEi (pairwise comparison, group × time interaction with Bonferroni’s correction).

Fig. 4.

LV mass (A) and posterior wall thickness (B) in SH, nT, and three treated groups estimated by bimonthly Echo during 12 months after induction of MI in all animals. ∗, p < 0.05 versus SH; †, p < 0.05 versus nT (pairwise comparison, group × time interaction with Bonferroni’s correction).

Fig. 5.

Representative pressure-volume loops of SH, nT, and three treated groups recorded at the end of the study.