The present study was carried out to determine if the beneficial effects of carvedilol in congestive heart failure are mediated via its -adrenergic blocking, antioxidant, and/or -adrenergic blocking action. Rabbits with heart failure induced by rapid cardiac pacing were randomized to receive subcutaneous carvedilol, metoprolol, propranolol plus doxazosin or placebo pellets for 8 weeks, and compared to sham-operated rabbits without pacing. We found that rapid cardiac pacing produced clinical heart failure, left ventricular dilation and decline of left ventricular fractional shortening. This was associated with an increase in left ventricular end-diastolic pressure, decrease in left ventricular dP/dt and myocyte hypertrophy. Tissue oxidative stress, measured by the ratio of reduced to oxidized glutathione (GSH/GSSG), was increased in the heart, along with increased oxidation product of mitochondrial DNA, 8-oxo-dG, increase of Bax, decrease of Bcl-2 and increase of apoptotic myocytes as measured by anti-single stranded DNA monoclonal antibody. Administration of carvedilol and metoprolol, which had no effects in Sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which have less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, the GSH/GSSG ratio correlated significantly with the changes of left ventricular end-diastolic dimension (r=-0.678, P<0.0001), fractional shortening (r=0.706, P<0.0001), and apoptotic myocytes (r=-0.473, P=0.0001). Thus, our findings suggest that the antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of the clinical beneficial effects of the -receptors in the treatment of CHF.