title: Cardioprotective effects of carvedilol on acute autoimmune myocarditis: anti-inflammatory effects associated with antioxidant property.
abstract: Carvedilol, a new beta-blocker with antioxidant properties, has been shown to be cardioprotective in experimental models of myocardial damage. We investigated whether carvedilol protects against experimental autoimmune myocarditis (EAM) because of its suppression of inflammatory cytokines and its antioxidant properties. We orally administered a vehicle, various doses of carvedilol, racemic carvedilol [R(+)-carvedilol, an enantiomer of carvedilol without beta-blocking activity], metoprolol, or propranolol to rats with EAM induced by porcine myosin for 3 wk. Echocardiographic study showed that the three beta-blockers, except R(+)-carvedilol, suppressed left ventricular fractional shortening and decreased heart rates to the same extent. Carvedilol and R(+)-carvedilol, but not metoprolol or propranolol, markedly reduced the severity of myocarditis at the two different doses and suppressed thickening of the left ventricular posterior wall in rats with EAM. Only carvedilol suppressed myocardial mRNA expression of inflammatory cytokines and IL-1beta protein expression in myocarditis. In addition, carvedilol and R(+)-carvedilol decreased myocardial protein carbonyl contents and myocardial thiobarbituric acid-reactive substance products in rats with EAM. The in vitro study showed that carvedilol and R(+)-carvedilol suppressed IL-1beta production in LPS-stimulated U937 cells and that carvedilol and R(+)-carvedilol, but not metoprolol or propranolol, suppressed thiobarbituric acid-reactive substance products in myocardial membrane challenged by oxidative stress. It was also confirmed that probucol, an antioxidant, ameliorated EAM in vivo. Carvedilol protects against acute EAM in rats, and the superior cardioprotective effect of carvedilol compared with metoprolol and propranolol may be due to suppression of inflammatory cytokines associated with the antioxidant properties in addition to the hemodynamic modifications.
authors.affiliation: Dept. of Cardiovascular Medicine, Graduate School of Medicine, Kyoto Univ., 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shioji
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takenaka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Onozawa
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kishimoto
mesh_terms: D000208:Acute Disease; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000473:pathology* / Q000503:physiopathology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002227:Carbazoles / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077261:Carvedilol; D006339:Heart Rate / Q000187:drug effects; D008790:Metoprolol / Q000494:pharmacology; D009205:Myocarditis / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D023282:Nuclease Protection Assays; D009929:Organ Size / Q000187:drug effects; D011412:Propanolamines / Q000494:pharmacology*; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D012260:Ribonucleases; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002227:Carbazoles; D002316:Cardiotonic Agents; D011412:Propanolamines; D017392:Thiobarbituric Acid Reactive Substances; D000077261:Carvedilol; D011433:Propranolol; D012260:Ribonucleases; D008790:Metoprolol