Suppression of myocardial ischemia-reperfusion injury by inhibitors of cytochrome P450 in rats.

ABSTRACT

The effects of inhibitors of cytochrome P450 on myocardial regional ischemia-reperfusion injury were examined in rats. Ischemia-reperfusion injury was evoked by ligation of the left anterior descending coronary artery for 1 h, followed by reperfusion for 24 h. Injuries were evident in causing infarction, decreases in left ventricular systolic pressure and left ventricle (dP/dt max)/P and an increase in left ventricular end-diastolic pressure. Increases in lipid peroxidation and reactive oxygen species levels in the ischemic region were observed. Intravenous injection of the potent cytochrome P450 inhibitor sulfaphenazole at 10 and 30 mg/kg at the time of reperfusion reduced infarct size by 41.7 and 73.2%, respectively; and improved cardiac function accompanied by the decrease in content of lipid peroxide and reactive oxygen species in the area at risk. Cardiac testosterone metabolism was inhibited by sulfaphenazole administration, indicating its inhibitory effects on cardiac cytochrome P450 activity. Another cytochrome P450 inhibitor, cimetidine, given intravenously, had similar effects to sulfaphenazole on reperfusion injury. Taken together, these results indicate that reactive oxygen species derived from cytochrome P450 play an important part in myocardial regional ischemia-reperfusion injury in vivo, and strongly support the hypothesis that cytochrome P450 inhibitors are promising therapeutic agents for cardiac ischemia-reperfusion injury.