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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 18, 2006; DOI: 10.1124/jpet.105.099432

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Received for publication December 6, 2005.
Revised January 12, 2006.
Accepted for publication January 17, 2006.

{beta}-2 Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy

Steve Xydas 1, Aftab R. Kherani 1, Jonathan S. Chang 1, Stefan Klotz 1, Ilan Hay 1, Christopher J. Mutrie 1, Garrett W. Moss 1, Anguo Gu 1, Allison R. Schulman 1, Daqing Gao 2, Debora Hu 3, Chiming Wei 2, Mehmet C. Oz 1, Jie Wang 1*

1 Columbia University College of Physicians and Surgeons 2 Johns Hopkins University School of Medicine 3 Bernards High School

* Address correspondence to: E-mail: jwang{at}crf.org

Abstract

The benefit of the {beta}2-adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic HF is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis, and has synergy with a {beta}1-antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1)HF only; 2)HF+Clenbuterol; 3)HF+Metoprolol; 4)HF+Clenbuterol+Metoprolol; and 5)rats with sham surgery. HF was induced by LAD artery ligation and confirmed by decreased left ventricular fractional shortening, decreased dP/dtmax and elevated LVEDP, compared to Sham rats (p<0.01). After 9 weeks of oral therapy, echocardiographic, hemodynamic, and ex vivo end-diastolic pressure-volume relationship (EDPVR) measurements were obtained. Immunohistochemistry was performed for myocardial apoptosis and DNA damage markers. Levels of calcium-handling proteins were assessed by Western blot analysis. Clenbuterol-treated HF rats had increased weight gain and heart weights vs HF rats (p<0.05). EDPVR curves revealed a leftward shift in clenbuterol rats vs metoprolol and HF rats (p<0.05). The metoprolol-treated group had a lower LVEDP and higher dP/dtmax vs the HF group (p<0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers vs HF rats (all p<0.01). Protein levels of the ryanodine receptor and SERCA2a were improved in clenbuterol-, metoprolol-, and clenbuterol+metoprolol-treated groups vs HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterol+metoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.


Key words: apoptosis, calcium homeostasis, cardiomyopathy, clenbuterol, heart failure, remodeling


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