Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak.
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) x mg(-1) x 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.
Cardiovascular Research Group, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
M
M
Taniguchi
C
C
Wilson
C A
CA
Hunter
D J
DJ
Pehowich
A S
AS
Clanachan
G D
GD
Lopaschuk
D000255:Adenosine Triphosphate / Q000378:metabolism; D000332:Aerobiosis; D000818:Animals; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D000255:Adenosine Triphosphate; D003999:Dichloroacetic Acid