title: A comparison of carvedilol and metoprolol antioxidant activities in vitro.
abstract: Carvedilol is a vasodilating beta-blocker and antioxidant approved for treatment of mild to moderate hypertension. angina, and congestive heart failure. Metoprolol is a beta1-selective adrenoceptor antagonist. When carvedilol and metoprolol were recently compared in clinical trials for heart failure, each showed beneficial beta-blocker effects such as improved symptoms, quality of life, exercise tolerance, and ejection fraction, with no between-group differences. When thiobarbituric acid reactive substance (TBARS) levels were measured in serum as an indirect marker of free radical activity, there were also no between-group differences. However, we had noted superior cardioprotection by carvedilol in comparison to metoprolol in ischemia and reperfusion models. We therefore examined antioxidant activity directly in cells and tissues. Here we show that in cultured rat cerebellar neurons, and in brain and heart membranes, carvedilol has far greater antioxidant activity than metoprolol, which is essentially inactive as an antioxidant in these model systems. The antioxidant activity of carvedilol could be explained by a greater degree of lipophilicity, as measured by its ClogP value of 3.841 as contrasted to a ClogP value of 1.346 for metoprolol. Alternatively, the molecular structure of carvedilol favors redox recycling, which the structure of metoprolol does not. Therefore, carvedilol could have additional pharmacologic effects that are favorable for long-term therapy.
authors.affiliation: Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA. Paul_G_Lysko@sbphrd.com
authors.forename: P G
authors.initials: PG
authors.lastname: Lysko
authors.forename: C L
authors.initials: CL
authors.lastname: Webb
authors.forename: J L
authors.initials: JL
authors.lastname: Gu
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
authors.forename: R R
authors.initials: RR
authors.lastname: Ruffolo
authors.forename: T L
authors.initials: TL
authors.lastname: Yue
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D005609:Free Radicals / Q000737:chemistry; D006321:Heart / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008790:Metoprolol / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D000975:Antioxidants; D002227:Carbazoles; D005609:Free Radicals; D011412:Propanolamines; D017392:Thiobarbituric Acid Reactive Substances; D000077261:Carvedilol; D008790:Metoprolol