The mechanisms by which β-adrenergic receptor (β-AR) blockade modulates apoptosis in heart failure (HF) are unclear. We examined the impact of β-AR blockade with metoprolol on myocardial remodeling, apoptosis, pro-apoptotic (Fas, Fas ligand, Bax, and Bcl-XS) and anti-apoptotic (Bcl-XLand Bcl-2) gene expression, and Bcl-XLand Bcl-XSprotein in post-infarction HF in rats. In untreated rats, there was significant (P < 0.001) LV dilatation and systolic dysfunction compared to sham. Myocardial apoptosis was significantly increased (P < 0.005). Fas, Bax, and Bcl-2 mRNA expression was unchanged. However, Fas ligand mRNA and Bcl-XSmRNA and protein, all undetectable in sham, were markedly elevated (P < 0.001), whereas Bcl-XLmRNA and protein was unchanged. Immunohistochemistry confirmed increased Bcl-XSstaining in failing myocardium, with unchanged Bcl-XL. Metoprolol treatment resulted in: (1) improved LV remodeling (P < 0.025), (2) reduced myocardial apoptosis (P < 0.005), and (3) selective reduction in myocardial Bcl-XSexpression (P < 0.001) without change in Fas, Fas ligand, Bax, Bcl-2, or Bcl-XL. Studies in isolated rat myocytes revealed that prolonged isoproterenol (ISO) stimulation significantly increased Bcl-XSprotein, reducing the Bcl-XL/XSratio and myocyte survival (P < 0.005). ISO-induced Bcl-XSexpression was significantly attenuated (P < 0.001) by both metoprolol and CGP20712A, a β1-AR selective antagonist, but not by ICI118,551, a β2-AR selective antagonist. We conclude that adrenergic activation, such as occurs in HF, increases pro-apoptotic Bcl-XSexpression via the β1-AR. β-AR blockade in HF reduces myocardial apoptosis; attenuation of Bcl-XSexpression may be one mechanism underlying this effect. © 2003 Elsevier Science Ltd. All rights reserved.