Increased mitochondrial KATP channel activity during chronic myocardial hypoxia -: Is cardioprotection mediated by improved bioenergetics?

Increased resistance to myocardial ischemia in chronically hypoxic immature rabbit hearts is associated with activation of ATP-sensitive K+ (K-ATP) channels. We determined whether chronic hypoxia from birth alters the function of the mitochondrial K-ATP. channel. The K-ATP channel opener bimakalim (1 mu mol/L) increased postischemic recovery of left ventricular developed pressure in isolated normoxic (F-IO2=0.21) hearts to values (42+/-4% to 67+/-5%) not different from those of hypoxic controls but did not alter postischemic recovery of developed pressure in isolated chronically hypoxic (F-IO2=0.12) hearts (69+/-5% to 72+/-5%). Conversely, the K-ATP channel blockers glibenclamide (1 mu mol/L) and 5-hydroxydecanoate (5-HD, 300 mu mol/L) attenuated the cardioprotective effect of hypoxia but had no effect on postischemic recovery of function in normoxic hearts. ATP synthesis rates in hypoxic heart mitochondria (3.92+/-0.23 mu mol ATP.min(-1).mg mitochondrial protein(-1)) were significantly greater than rates in normoxic hearts (2.95+/-0.08 mu mol ATP.min(-1).mg mitochondrial protein(-1)). Bimakalim (1 mu mol/L) decreased the rate of ATP synthesis in normoxic heart mitochondria consistent with mitochondrial K-ATP channel activation and mitochondrial depolarization. The effect of bimakalim on ATP synthesis was antagonized by the K-ATP channel blockers glibenclamide (1 mu mol/L) and 5-HD (300 mu mol/L) in normoxic heart mitochondria, whereas glibenclamide and 5-HD alone had no effect. In hypoxic heart mitochondria, the rate of ATP synthesis was not affected by bimakalim but was attenuated by glibenclamide and 5-HD. We conclude that mitochondrial K-ATP channels are activated in chronically hypoxic rabbit hearts and implicate activation of this channel in the improved mitochondrial bioenergetics and cardioprotection observed.