Role of an ATP-sensitive potassium channel opener, YM934, in mitochondrialenergy production in ischemic/reperfused heart

We examined a possible mechanism of action of an ATP-sensitive potassium (K -ATP) channel opener, YM934, for the improvement of energy metabolism in he arts subjected to 35-min ischemia and 60-min reperfusion. The treatment wit h 30 nM YM934 for the final 15 min of preischemia enhanced postischemic rec overy of left ventricular developed pressure, attenuated the postischemic r ise in left ventricular end-diastolic pressure, and suppressed the release of creatine kinase and ATP metabolites during reperfusion. The treatment al so restored myocardial ATP and creatine phosphate contents and attenuated t he decrease in mitochondrial oxygen consumption rate during reperfusion. Th e higher mitochondrial function was also seen in YM934-treated hearts at th e end of ischemia. In another set of experiments, myocardial skinned bundle s were incubated for 30 min under hypoxic conditions in the presence and ab sence of YM934, and then mitochondrial oxygen consumption rate was determin ed. Hypoxia decreased the mitochondrial oxygen consumption rate of skinned bundles to approximately 40% of the prehypoxic value. In contrast, the trea tment of skinned bundles with 30 nM YM934 preserved the mitochondrial oxyge n consumption rate during hypoxia. The effect of YM934 on the hypoxic skinn ed bundles was abolished by combined treatment with either the K-ATP channe l blocker glyburide or the mitochondrial K-ATP channel blocker 5-hydroxydec anoate in a concentration-dependent manner. The results suggest that YM934 is capable of attenuating ischemia/reperfusion injury of isolated perfused hearts due to preservation of mitochondrial function during ischemia, proba bly through opening of mitochondrial K-ATP channels.