PT  - JOURNAL ARTICLE
AU  - Ruijuan Wang
AU  - Toshiro Miura
AU  - Nozomu Harada
AU  - Ryosuke Kametani
AU  - Masaki Shibuya
AU  - Yasuhiro Fukagawa
AU  - Shuji Kawamura
AU  - Yasuhiro Ikeda
AU  - Masayuki Hara
AU  - Masunori Matsuzaki
TI  - Pleiotropic Effects of the β-Adrenoceptor Blocker Carvedilol on Calcium Regulation during Oxidative Stress-Induced Apoptosis in Cardiomyocytes
AID  - 10.1124/jpet.105.099903
DP  - 2006 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 45--52
VI  - 318
IP  - 1
4099  - http://jpet.aspetjournals.org/content/318/1/45.short
4100  - http://jpet.aspetjournals.org/content/318/1/45.full
SO  - J Pharmacol Exp Ther2006 Jul 01; 318
AB  - Carvedilol is a nonselective β-adrenoceptor blocker with multiple pleiotropic actions. A recent clinical study suggested that carvedilol may be superior to other β-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 (ΔΨm) 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 ΔΨm dissipation and the induction of apoptosis. Carvedilol (10 μM) significantly delayed these processes and reduced apoptosis. These effects were not observed with other β-adrenoceptor blockers (metoprolol, atenolol, and propranolol) or with a combination of the α (phentolamine)- and the β-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 ΔΨm is independent of α- and β-adrenoceptors but is probably dependent on the antioxidant effect. The American Society for Pharmacology and Experimental Therapeutics