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CARDIOVASCULAR

Pleiotropic Effects of the -Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes

Division of Cardiology, Department of Medicine and Clinical Science (R.W., T.M., N.H., R.K., M.S., Y.F., S.K., M.M.) and Molecular Cardiovascular Biology (Y.I.), Yamaguchi University Graduate School of Medicine, Minami-Kogushi Ube, Yamaguchi, Japan; and General Isotope Center (M.H.), Tokyo Medical and Dental University, Yushima Bunkyo-ku, Tokyo, Japan

Carvedilol is a nonselective -adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other -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 µM), but not metoprolol (10 µM), reduced H₂O₂ (100 µM)-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 (_m) 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 _m dissipation and the induction of apoptosis. Carvedilol (10 µM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other -adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the (phentolamine)- and the -adrenoceptor blocker. The antioxidant N-acetyl-L-cysteine (NAC, 5 mM) and the combination of NAC and propranolol (10 µM) showed an effect similar to that of carvedilol. Therefore, the effect of carvedilol on H₂O₂-induced changes in [Ca²⁺]_m, [Ca²⁺]_i, and _m is independent of - and -adrenoceptors but is probably dependent on the antioxidant effect.

Address correspondence to: Dr. Toshiro Miura, 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. E-mail: toshiro{at}yamaguchi-u.ac.jp