Increased Mitochondrial K ATP Channel Activity During Chronic Myocardial Hypoxia

Abstract

Abstract —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 μmol/L) increased postischemic recovery of left ventricular developed pressure in isolated normoxic (F io 2 =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 io 2 =0.12) hearts (69±5% to 72±5%). Conversely, the K ATP 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 K ATP channel activation and mitochondrial depolarization. The effect of bimakalim on ATP synthesis was antagonized by the K ATP 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 K ATP channels are activated in chronically hypoxic rabbit hearts and implicate activation of this channel in the improved mitochondrial bioenergetics and cardioprotection observed.