Increased mitochondrial K-ATP 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) ch annels. We determined whether chronic hypoxia from birth alters the functio n of the mitochondrial K-ATP. channel. The K-ATP channel opener bimakalim ( 1 mu mol/L) increased postischemic recovery of left ventricular developed p ressure 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 postisc hemic 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) atte nuated the cardioprotective effect of hypoxia but had no effect on postisch emic recovery of function in normoxic hearts. ATP synthesis rates in hypoxi c heart mitochondria (3.92+/-0.23 mu mol ATP.min(-1).mg mitochondrial prote in(-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 consist ent with mitochondrial K-ATP channel activation and mitochondrial depolariz ation. The effect of bimakalim on ATP synthesis was antagonized by the K-AT P channel blockers glibenclamide (1 mu mol/L) and 5-HD (300 mu mol/L) in no rmoxic heart mitochondria, whereas glibenclamide and 5-HD alone had no effe ct. In hypoxic heart mitochondria, the rate of ATP synthesis was not affect ed by bimakalim but was attenuated by glibenclamide and 5-HD. We conclude t hat mitochondrial K-ATP channels are activated in chronically hypoxic rabbi t hearts and implicate activation of this channel in the improved mitochond rial bioenergetics and cardioprotection observed.