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

Abstract

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 on the mitochondrial function and reactive oxygen species (ROS) production during Ca2+ overload was investigated. Methods and Results: The mitochondrial oxygen consumption (mV̇O2) and the mitochondrial ROS production in isolated rat heart mitochondria was measured. Ca2+ overload from 10 to 100 μmol/L augmented mV̇O2 was from 527±139 to 671±138 nmol/mg (p<0.05), and this was then completely suppressed by carvedilol (1 μmol/L), but not by metoprolol (100 μmol/L). Ca2+ overload augmented the ROS production upon complex I injury (9.7±1.2 to 11.4±1.4 nmol/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 mV̇O2 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.