Protective effects of 5(S)-5-carboxystrictosidine on myocardial ischemia-reperfusion injury through activation of mitochondrial KATP channels

Abstract

5(S)-5-carboxystrictosidine (5-CS) is a compound found in Mappianthus iodoides Hand.-Mazz., root, a traditional Chinese medicine used for the treatment of coronary artery disease. In this study, we investigated whether 5-CS protects heart against I/R injury. Sprague–Dawley rats were treated with 5-CS intraperitoneally for 7 days before the experiment. Hearts were perfused for 20 min global ischemia and 180 min reperfusion. 5-CS significantly inhibited an increase in the post-ischemic left ventricular end-diastolic pressure (LVEDP) and improved the post-ischemic left ventricular developed pressure (LVDP), dP/dt maximum and dP/dt minimum rates of pressure change, and coronary flow as compared with sham group. Pretreatment with 5-hydroxydecanoic acid (5-HD), an inhibitor of mitochondrial KATP channel, for 10 min before ischemia attenuated the improvement of LVEDP, LVDP, dP/dt maximum and dP/dt minimum rates of pressure change, and coronary flow induced by 5-CS. 5-CS markedly decreased the infarct size and attenuated the increased lactate dehydrogenase (LDH) level in effluent during reperfusion. Pretreatment with 5-HD also blocked these protective effects of 5-CS. 5-CS increased Mn-SOD, catalase, and HO-1 levels decreased by I/R injury and pretreatment of 5-HD blocked the 5-CS effects. Increases in Bax, cleaved caspase-3 and cytochrome c levels, caspase-3 and caspase-9 activity, and decrease in Bcl-2 level by I/R injury were attenuated by 5-CS treatment and pretreatment of 5-HD blocked its effects. These results suggest that the protective effects of 5-CS against myocardial I/R injury may be partly related to activating antioxidant enzymes and suppressing apoptosis through opening mitochondrial KATP channels.