Published Online
on August 16, 2004

A more recent version of this article appeared on August 31, 2004

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Submitted on October 14, 2003
Revised on March 13, 2004
Accepted on March 26, 2004

Beneficial Effects of Chronic Pharmacological Manipulation of -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, and Mark I. Talan MD, PhD^*

From the Gerontology Research Center, Baltimore, Md.

^* To whom correspondence should be addressed. E-mail: talanm{at}grc.nia.nih.gov.

Background--Studies in isolated cardiac myocytes have demonstrated that signaling via specific ₁-adrenergic receptor subtypes (₁ARs) promotes but that signaling via ₂ARs protects from cell death. We hypothesized that prolonged ₂AR stimulation or ₁AR 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 ₂AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The ₁AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the ₂AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by ₂AR agonists than by the ₁AR blocker. Both ₂AR agonists and the ₁AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the ₂AR agonists reduced the Eed and the MI size by reducing infarct expansion.

Conclusions--These results provide proof of concept for the efficacy of chronic ₂AR stimulation in this DCM model.

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

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