Faculty Collaboration Database

Increased mitochondrial K(ATP) channel activity during chronic myocardial hypoxia: is cardioprotection mediated by improved bioenergetics? Circ Res 2000 Nov 10;87(10):915-21

Date

11/14/2000

Pubmed ID

11073888

DOI

10.1161/01.res.87.10.915

Scopus ID

2-s2.0-0034634296 (requires institutional sign-in at Scopus site)   65 Citations

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.

Author List

Eells JT, Henry MM, Gross GJ, Baker JE

Authors

John E. Baker PhD Professor in the Surgery department at Medical College of Wisconsin
Janis Eells PhD Professor in the Biomedical Sciences department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

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