title: Pleiotropic effects of the beta-adrenoceptor blocker carvedilol on calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes.
abstract: Carvedilol is a nonselective beta-adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other beta-adrenoceptor blockers in the treatment of heart failure. Despite numerous investigations, the underlying mechanisms of carvedilol on improving heart failure are yet to be fully established. The purpose of this study is to clarify the pleiotropic effect of carvedilol on cytosolic and mitochondrial calcium regulation during oxidative stress-induced apoptosis in cardiomyocytes. Carvedilol (10 microM), but not metoprolol (10 microM), reduced H2O2 (100 microM)-induced apoptosis in neonatal rat cardiomyocytes. During the process, changes in cytosolic calcium concentration ([Ca2+]i) and mitochondrial calcium concentration ([Ca2+]m) and mitochondrial membrane potential (DeltaPsim) were measured by fluorescent probes [Fluo-3/acetoxymethyl ester (AM), Rhod-2/AM, and tetramethylrhodamine ethyl ester, respectively] and imaged by laser confocal microscopy. The results showed that H2O2 caused [Ca2]m overload first, followed by [Ca2+]i overload, leading to DeltaPsim dissipation and the induction of apoptosis. Carvedilol (10 microM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other beta-adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the alpha (phentolamine)- and the beta-adrenoceptor blocker. The antioxidant N-acetyl-L-cysteine (NAC, 5 mM) and the combination of NAC and propranolol (10 microM) showed an effect similar to that of carvedilol. Therefore, the effect of carvedilol on H2O2-induced changes in [Ca2+]m, [Ca2+]i, and DeltaPsi(m) is independent of alpha- and beta-adrenoceptors but is probably dependent on the antioxidant effect.
authors.affiliation: Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505 Japan.
authors.forename: Ruijuan
authors.initials: R
authors.lastname: Wang
authors.forename: Toshiro
authors.initials: T
authors.lastname: Miura
authors.forename: Nozomu
authors.initials: N
authors.lastname: Harada
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kametani
authors.forename: Masaki
authors.initials: M
authors.lastname: Shibuya
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fukagawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Kawamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hara
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D002118:Calcium