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(Circulation Research. 2000;87:915.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Increased Mitochondrial K_ATP Channel Activity During Chronic Myocardial Hypoxia

Is Cardioprotection Mediated by Improved Bioenergetics?

Janis T. Eells, Michele M. Henry, Garrett J. Gross, John E. Baker

From the Department of Pharmacology and Toxicology (J.T.E., M.M.H., G.J.G., J.E.B.), Division of Pediatric Surgery (J.E.B.), Medical College of Wisconsin, Milwaukee, Wis.

Correspondence to Janis T. Eells, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail jeells{at}mcw.edu

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 (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 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.

Key Words: chronic hypoxia • 5-hydroxydecanoate • mitochondrial K_ATP channel

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