Carbon monoxide-releasing molecules attenuate postresuscitation myocardial injury and protect cardiac mitochondrial function by reducing the production of mitochondrial reactive oxygen species in a rat model of cardiac arrest.

The objective of this study is to examine whether carbon monoxide-releasing molecules (CORMs) can decrease the generation of excessive reactive oxygen species (ROS) in cardiac mitochondria, thereby protecting against postresuscitation myocardial injury and cardiac mitochondrial dysfunction after resuscitation in a rat model of ventricular fibrillation (VF), and further investigated the underlying mechanism. Rats suffered 8 minutes of untreated VF and resuscitation and were randomized into the control group with vehicle infusion and the CORM group with CO-releasing molecule 2 (CORM2) treatment. Animals in the Sham group were instrumented without induced VF and resuscitation. Effects of CORM2 on cardiac function, myocardial oxidative stress, cardiac mitochondrial function, and mitochondrial ROS generation were assessed. Moreover, to further evaluate the direct effect of CORM2 on cardiac mitochondria isolated from resuscitated rats, we measured mitochondrial function and ROS generation when isolated cardiac mitochondria were directly incubated with different concentrations of (CORM2). Compared with the Sham group, the control and CORM groups demonstrated impaired cardiac function, increased myocardial injury, and aggravated mitochondrial damage. CORM2 improved cardiac performance and attenuated myocardial damage and oxidative stress in resuscitated rats. Additionally, animals with CORM2 treatment showed the decreased generation of cardiac mitochondrial ROS, alleviated mitochondrial injury, and preserved mitochondrial function and complex activities when compared with the control group. In isolated cardiac mitochondria incubated with CORM2, low concentrations of CORM2 (20 μmol/L) mildly uncoupled mitochondrial respiration, leading to reduced mitochondrial ROS production. In contrast, high concentrations of CORM2 (60 μmol/L) resulted in the reverse effect presumably due to its excessive uncoupling action. These findings suggest that CORM2 attenuates oxidative stress of the heart and improves cardiac function after resuscitation. The mechanism was probably that CO, the product of CORM2, reduces the production of cardiac mitochondrial ROS and thereby attenuates mitochondrial injury and dysfunction during the postresuscitation period, due to the transient uncoupling of mitochondrial respiration.