Carvedilol inhibits mitochondrial oxygen consumption and superoxide production during calcium overload in isolated heart mitochondria

Background The COMET study suggested the better effect of carvedilol to metoprolol in treating heart failure. However, its underlying mechanisms of action remain unclear. As a result, evaluation of the distinct effects of both drugs oil the mitochondrial function and reactive oxygen species (ROS) production during Ca2+ overload was investigated. Methods and Results The mitochondrial oxygen consumption (mVO(2)) and the mitochondrial ROS production in isolated rat heart mitochondria was measured. Ca2+ overload from 10 to 100/mu mol/L augmented mVO(2) was from 527 +/- 139 to 671 +/- 138 mnol/mg (p<0.05), and this was then completely suppressed by carvedilol (1 mu mol/L), but not by metoprolol (100 mu mol/L). Ca2+ overload augmented the ROS production upon complex I injury (9.7 +/- 1.2 to 11.4 +/- 1.4nmol/mg, p < 0.05). Carvedilol dose-dependently suppressed this ROS production, whereas metoprolol did not. Conclusions Carvedilol, but not metoprolol, was thus found to inhibit the calcium-dependent augmentation of mVO(2) and ROS production upon complex I injury. This new effect of carvedilol might partly explain the beneficial effect of carvedilol for the treatment of heart failure.