The benefit of the  2 -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  1 antagonist, metoprolol, in a model of ischemic HF. Rats were randomized to: 1) HF only; 2) HF ϩ clenbuterol; 3) HF ϩ metoprolol; 4) HF ϩ clenbuterol ϩ 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/dt max ), and elevated left ventricular end-diastolic pressure (LVEDP) compared with sham rats (p Ͻ 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 Ͻ 0.05). EDPVR curves revealed a leftward shift in clenbuterol rats versus metoprolol and HF rats (p Ͻ 0.05). The metoprololtreated group had a lower LVEDP and higher dP/dt max versus the HF group (p Ͻ 0.05). Clenbuterol and metoprolol groups had decreased myocardial apoptosis and DNA damage markers and increased DNA repair markers versus HF rats (all p Ͻ 0.01). Protein levels of the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase were improved in clenbuterol-, metoprolol-, and clenbuterolϩmetoprolol-treated groups versus HF rats. However, as a combination therapy, there were no synergistic effects of clenbuterolϩmetoprolol treatment. We conclude that clenbuterol ameliorates EDPVR, apoptosis, and calcium homeostasis but does not have synergy with metoprolol in our model of ischemic HF.Clenbuterol is a  2 -adrenergic receptor agonist first used in the mid-1970s to treat asthma and is approved for this indication in Europe (Salorinne et al., 1975). The drug bears structural similarity to albuterol but has enhanced oral absorption and  2 -selectivity. Clenbuterol also increases muscle bulk (Choo et al., 1992;Maltin et al., 1993;Carter and Lynch, 1994) because of an anabolic effect that may be mediated via long-term  2 -activation (MacLennan and Edwards, 1989;Choo et al., 1992). Because of this anabolic action, oral clenbuterol has been abused by athletes to enhance size and strength (Beckett, 1992;Perry, 1993). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
