TY - JOUR T1 - β<sub>2</sub>-Adrenergic Stimulation Attenuates Left Ventricular Remodeling, Decreases Apoptosis, and Improves Calcium Homeostasis in a Rodent Model of Ischemic Cardiomyopathy JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 553 LP - 561 DO - 10.1124/jpet.105.099432 VL - 317 IS - 2 AU - Steve Xydas AU - Aftab R. Kherani AU - Jonathan S. Chang AU - Stefan Klotz AU - Ilan Hay AU - Christopher J. Mutrie AU - Garrett W. Moss AU - Anguo Gu AU - Allison R. Schulman AU - Daqing Gao AU - Debora Hu AU - Ed X. Wu AU - Chiming Wei AU - Mehmet C. Oz AU - Jie Wang Y1 - 2006/05/01 UR - http://jpet.aspetjournals.org/content/317/2/553.abstract N2 - 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 &lt; 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 &lt; 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p &lt; 0.05). The metoprolol-treated group had a lower LVEDP and higher dP/dtmax versus the HF group (p &lt; 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p &lt; 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. The American Society for Pharmacology and Experimental Therapeutics ER -