Abstract
The benefit of the β2-adrenergic agonist, clenbuterol, in left ventricular assist device patients with dilated cardiomyopathy has been reported, but its effect on ischemic heart failure (HF) is unknown. We investigated whether clenbuterol improves left ventricular remodeling, myocardial apoptosis and has synergy with a β1 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 left anterior descending artery (LAD) artery ligation and confirmed by decreased left ventricular fractional shortening, decreased maximum left ventricular dP/dt (dP/dtmax), and elevated left ventricular end-diastolic pressure (LVEDP) compared with 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 versus HF rats (p < 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p < 0.05). The metoprolol-treated group had a lower LVEDP and higher dP/dtmax versus the HF group (p < 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p < 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterol+metoprolol-treated groups versus 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.
Footnotes
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This study was supported in part by a resident training grant from the Department of Surgery, Columbia University College of Physicians and Surgeons and was supported in part by the Ministry of Education of the People's Republic of China (IRT0430).
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Results from this study were partially presented at the American Heart Association Scientific Sessions 2004; Nov 7–10, 2004; New Orleans, LA: Xydas S, Klotz S, Hay I, Chang JS, Mutrie C, Gao D, Chen L, Ng C, Wang J, and Wei C (2004) Additive effects of β-1 adrenergic antagonism and β-2 stimulation on myocardial apoptotic inhibition and DNA repair in a model of congestive heart failure (Abstract). Circulation110 (Suppl): III–5.
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doi:10.1124/jpet.105.099432.
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ABBREVIATIONS: SERCA2a, sarcoplasmic reticulum calcium-ATPase; LAD, left anterior descending artery; Clen+Meto, clenbuterol and metoprolol; EDPVR, end-diastolic pressure-volume relationship; LVEDP, left ventricular end-diastolic pressure; dP/dtmax, maximum left ventricular dP/dt; dP/dtmin, minimum left ventricular dP/dt; TUNEL, terminal deoxynucleotidyltransferase end labeling; 8-oxoG, 8-oxo-7,8-dihydrodeoxyguanine; SERCA2a, sarcoplasmic reticulum calcium-ATPase.
- Received December 3, 2005.
- Accepted January 17, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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