Beneficial Effects of Chronic Pharmacological Manipulation of β-Adrenoreceptor Subtype Signaling in Rodent Dilated Ischemic Cardiomyopathy

Abstract

Background— Studies in isolated cardiac myocytes have demonstrated that signaling via specific β 1 -adrenergic receptor subtypes (β 1 ARs) promotes but that signaling via β 2 ARs protects from cell death. We hypothesized that prolonged β 2 AR stimulation or β 1 AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure. Methods and Results— A large myocardial infarction (MI) induced in rats by coronary artery ligation resulted in a dilated cardiomyopathy (DCM) characterized by infarct expansion and a progressive increase in left ventricular (LV) end-diastolic volume, accompanied by a reduction in ejection fraction (EF), as assessed by repeated echocardiography. Pressure-volume analysis at 8 weeks after ligation showed that diastolic stiffness (Eed) and arterial elastance (Ea) were increased, end-systolic elastance (Ees) was decreased, and arterioventricular (AV) coupling (Ea/Ees) had deteriorated. Apoptosis was present in both peri-infarct and remote myocardium. Chronic (6-week) administration of the β 2 AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The β 1 AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the β 2 AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by β 2 AR agonists than by the β 1 AR blocker. Both β 2 AR agonists and the β 1 AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the β 2 AR agonists reduced the Eed and the MI size by reducing infarct expansion. Conclusions— These results provide proof of concept for the efficacy of chronic β 2 AR stimulation in this DCM model.