Increased mitochondrial K(ATP) channel activity during chronic myocardial hypoxia: is cardioprotection mediated by improved bioenergetics?

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 micromol/L) increased postischemic recovery of left ventricular developed pressure in isolated normoxic (FIO(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 (FIO(2)=0.12) hearts (69+/-5% to 72+/-5%). Conversely, the K(ATP) channel blockers glibenclamide (1 micromol/L) and 5-hydroxydecanoate (5-HD, 300 micromol/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 micromol ATP. min(-1). mg mitochondrial protein(-1)) were significantly greater than rates in normoxic hearts (2.95+/-0.08 micromol ATP. min(-1). mg mitochondrial protein(-1)). Bimakalim (1 micromol/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 micromol/L) and 5-HD (300 micromol/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.

• Authors: J T Eells, M M Henry, G J Gross, J E Baker
• Journal: Circulation research (Circ Res) Vol. 87 Issue 10 Pg. 915-21 (Nov 10 2000) ISSN: 1524-4571 [Electronic] United States
• PMID: 11073888 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Benzopyrans
• Decanoic Acids
• Dihydropyridines
• Hydroxy Acids
• Potassium Channel Blockers
• Potassium Channels
• bimakalim
• 5-hydroxydecanoic acid
• Adenosine Triphosphate
• Glyburide

Topics

• Adaptation, Physiological (drug effects)
• Adenosine Triphosphate (metabolism)
• Animals
• Animals, Newborn
• Benzopyrans (pharmacology)
• Cell Hypoxia (physiology)
• Chronic Disease
• Cytoprotection (physiology)
• Decanoic Acids (pharmacology)
• Dihydropyridines (pharmacology)
• Energy Metabolism (drug effects, physiology)
• Glyburide (pharmacology)
• Heart Ventricles (metabolism)
• Hemodynamics (drug effects)
• Hydroxy Acids (pharmacology)
• Hypoxia (metabolism)
• In Vitro Techniques
• Membrane Potentials (drug effects)
• Mitochondria, Heart (drug effects, metabolism)
• Myocardial Ischemia (metabolism)
• Myocardium (metabolism)
• Potassium Channel Blockers
• Potassium Channels (agonists, metabolism)
• Rabbits