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(Circulation. 2004;110:1083-1090.)
© 2004 American Heart Association, Inc.

Original Articles

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

Ismayil Ahmet, MD PhD; Melissa Krawczyk, MS; Phillip Heller, PhD; Chanil Moon, MD PhD; Edward G. Lakatta, MD; Mark I. Talan, MD PhD

From the Gerontology Research Center, Baltimore, Md.

Correspondence to Mark I. Talan, MD, PhD, Gerontology Research Center, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail talanm{at}grc.nia.nih.gov

Received October 14, 2003; de novo received January 30, 2004; revision received March 13, 2004; accepted March 26, 2004.

Background— Studies in isolated cardiac myocytes have demonstrated that signaling via specific ß₁-adrenergic receptor subtypes (ß₁ARs) promotes but that signaling via ß₂ARs protects from cell death. We hypothesized that prolonged ß₂AR stimulation or ß₁AR 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 ß₂AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The ß₁AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the ß₂AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by ß₂AR agonists than by the ß₁AR blocker. Both ß₂AR agonists and the ß₁AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the ß₂AR agonists reduced the Eed and the MI size by reducing infarct expansion.

Conclusions— These results provide proof of concept for the efficacy of chronic ß₂AR stimulation in this DCM model.

Key Words: receptors, adrenergic, beta • heart failure • pharmacology • myocardial infarction • remodeling

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