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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, O2
consumption (nmol
O2 · mg
1 · min1)
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
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