title: Importance of antioxidant and antiapoptotic effects of beta-receptor blockers in heart failure therapy.
abstract: The present study was carried out to determine whether beneficial effects of carvedilol in congestive heart failure (CHF) are mediated via its beta-adrenergic blocking, antioxidant, and/or alpha-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 beta-receptors in the treatment of CHF.
authors.affiliation: Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawai
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.forename: Junya
authors.initials: J
authors.lastname: Shite
authors.forename: Weike
authors.initials: W
authors.lastname: Mao
authors.forename: Shuji
authors.initials: S
authors.lastname: Fukuoka
authors.forename: Chang-Seng
authors.initials: CS
authors.lastname: Liang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D048429:Cell Size; D004272:DNA, Mitochondrial / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004452:Echocardiography; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D006439:Hemodynamics; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011817:Rabbits; D012146:Rest; D051028:bcl-2-Associated X Protein
chemical_list: D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D004272:DNA, Mitochondrial; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D005978:Glutathione; D019803:Glutathione Disulfide