Published online before print August 16, 2004, doi: 10.1161/01.CIR.0000139844.15045.F9
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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
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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