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This Article Full Text Full Text (PDF) All Versions of this Article: 287/3/H1003    most recent 00797.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Kawai, K. Articles by Liang, C.-s. Search for Related Content PubMed PubMed Citation Articles by Kawai, K. Articles by Liang, C.-s.

Importance of antioxidant and antiapoptotic effects of -receptor blockers in heart failure therapy

Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642

Submitted 18 August 2003 ; accepted in final form 19 April 2004

The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) 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 wk and compared with sham-operated rabbits without pacing. We found 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 first derivative of left ventricular pressure, and myocyte hypertrophy. Tissue oxidative stress measured by GSH/GSSG was increased in the heart with increased oxidation product of mitochondrial DNA, 8-oxo-7,8-dihydro-2'-deoxyguanosine, 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 effect in sham animals, attenuated cardiac ventricular remodeling, cardiac hypertrophy, oxidative stress, and myocyte apoptosis in CHF. In contrast, propranolol plus doxazosin, which has less antioxidant effects, produced smaller effects on left ventricular function and myocyte apoptosis. In all animals, GSH/GSSG correlated significantly with 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 antioxidant and antiapoptotic actions of carvedilol and metoprolol are important determinants of clinical beneficial effects of -receptors in the treatment of CHF.

carvedilol; metoprolol; oxidative stress; myocytes apoptosis; myocyte hypertrophy.

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