Increased Mitochondrial K ATP Channel Activity During Chronic Myocardial Hypoxia

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Abstract
—Increased resistance to myocardial ischemia in chronically hypoxic immature rabbit hearts is associated with activation of ATP-sensitive K+ (KATP) channels. We determined whether chronic hypoxia from birth alters the function of the mitochondrial KATP channel. The KATP channel opener bimakalim (1 μmol/L) increased postischemic recovery of left ventricular developed pressure in isolated normoxic (Fio2=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 (Fio2=0.12) hearts (69±5% to 72±5%). Conversely, the KATP channel blockers glibenclamide (1 μmol/L) and 5-hydroxydecanoate (5-HD, 300 μmol/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 μmol ATP · min−1 · mg mitochondrial protein−1) were significantly greater than rates in normoxic hearts (2.95±0.08 μmol ATP · min−1 · mg mitochondrial protein−1). Bimakalim (1 μmol/L) decreased the rate of ATP synthesis in normoxic heart mitochondria consistent with mitochondrial KATP channel activation and mitochondrial depolarization. The effect of bimakalim on ATP synthesis was antagonized by the KATP channel blockers glibenclamide (1 μmol/L) and 5-HD (300 μmol/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 KATP channels are activated in chronically hypoxic rabbit hearts and implicate activation of this channel in the improved mitochondrial bioenergetics and cardioprotection observed.