Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak

1  Cardiovascular Research Group, 2  Division of Endocrinology and Metabolism, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2 Dichloroacetate (DCA) is a pyruvate dehydrogenase activator that increases cardiac efficiency during reperfusion of ischemic hearts. We determined whether DCA i...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2001-04, Vol.280 (4), p.H1762-H1769
Main Authors: Taniguchi, Masayuki, Wilson, Craig, Hunter, Charlene A, Pehowich, Daniel J, Clanachan, Alexander S, Lopaschuk, Gary D
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - metabolism
Aerobiosis
Animals
Dichloroacetic Acid - pharmacology
Heart - drug effects
Heart - physiology
Heart - physiopathology
Hydrogen-Ion Concentration
In Vitro Techniques
Intracellular Membranes - drug effects
Intracellular Membranes - physiology
Kinetics
Male
Membrane Potentials
Mitochondria, Heart - drug effects
Mitochondria, Heart - physiology
Myocardial Ischemia - physiopathology
Myocardial Reperfusion
Myocardial Reperfusion Injury - prevention & control
Oxidative Phosphorylation
Oxygen Consumption - drug effects
Rats
Rats, Sprague-Dawley
Time Factors
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Summary:1  Cardiovascular Research Group, 2  Division of Endocrinology and Metabolism, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2 Dichloroacetate (DCA) is a pyruvate dehydrogenase activator that increases cardiac efficiency during reperfusion of ischemic hearts. We determined whether DCA increases efficiency of mitochondrial ATP production by measuring proton leak in mitochondria from isolated working rat hearts subjected to 30 min of ischemia and 60 min of reperfusion. In untreated hearts, cardiac work and efficiency decreased during reperfusion to 26% and 40% of preischemic values, respectively. Membrane potential was significantly lower in mitochondria from reperfused (175.6 ± 2.2 mV) versus aerobic (185.8 ± 3.1 mV) hearts. DCA (1 mM added at reperfusion) improved recovery of cardiac work (1.9-fold) and efficiency (1.5-fold) but had no effect on mitochondrial membrane potential (170.6 ± 2.9 mV). At the maximal attainable membrane potential, O 2 consumption (nmol O 2 · mg 1 · min 1 ) did not differ between untreated or DCA-treated hearts (128.3   ± 7.5 and 120.6 ± 7.6, respectively) but was significantly greater than aerobic hearts (76.6 ± 7.6). During reperfusion, DCA increased glucose oxidation 2.5-fold and decreased H + production from glucose metabolism to 53% of untreated hearts. Because H + production decreases cardiac efficiency, we suggest that DCA increases cardiac efficiency during reperfusion of ischemic hearts by increasing the efficiency of ATP use and not by increasing the efficiency of ATP production. ischemia; pyruvate dehydrogenase
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.2001.280.4.h1762