We examined a possible mechanism of action of an
ATP-sensitive
potassium (K(
ATP)) channel opener,
YM934, for the improvement of energy metabolism in hearts subjected to 35-min
ischemia and 60-min reperfusion. The treatment with 30 nM
YM934 for the final 15 min of preischemia enhanced postischemic recovery of left ventricular developed pressure, attenuated the postischemic rise in left ventricular end-diastolic pressure, and suppressed the release of
creatine kinase and
ATP metabolites during reperfusion. The treatment also restored myocardial
ATP and
creatine phosphate contents and attenuated the decrease in mitochondrial oxygen consumption rate during reperfusion. The higher mitochondrial function was also seen in YM934-treated hearts at the end of
ischemia. In another set of experiments, myocardial skinned bundles were incubated for 30 min under hypoxic conditions in the presence and absence of
YM934, and then mitochondrial oxygen consumption rate was determined.
Hypoxia decreased the mitochondrial oxygen consumption rate of skinned bundles to approximately 40% of the prehypoxic value. In contrast, the treatment of skinned bundles with 30 nM
YM934 preserved the mitochondrial oxygen consumption rate during
hypoxia. The effect of
YM934 on the hypoxic skinned bundles was abolished by combined treatment with either the K(
ATP) channel blocker
glyburide or the
mitochondrial K(ATP) channel blocker
5-hydroxydecanoate 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, probably through opening of mitochondrial K(
ATP) channels.