EXPERIMENTAL STUDY
Dichloroacetate improves postischemic function of hypertrophied rat hearts
Richard B. Wambolt, BSc*,
Gary D. Lopaschuk, PhD ,
Roger W. Brownsey, PhD and
Michael F. Allard, BSc, MD*
* Department of Pathology and Laboratory Medicine, University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada
Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada
Manuscript received October 26, 1999;
revised manuscript received February 3, 2000,
accepted May 31, 2000.
Reprint requests and correspondence: Dr. Michael F. Allard, McDonald Research Laboratories, Room 292, St. Paul’s Hospital, 1081 Burrard Street, Vancouver, British Columbia, Canada V6Z 1Y6
mallard{at}mrl.ubc.ca
OBJECTIVES
We sought to determine whether improving coupling between glucose oxidation and glycolysis by stimulating glucose oxidation during reperfusion enhances postischemic recovery of hypertrophied hearts.
BACKGROUND
Low rates of glucose oxidation and high glycolytic rates are associated with greater postischemic dysfunction of hypertrophied as compared with nonhypertrophied hearts.
METHODS
Heart function, glycolysis and glucose oxidation were measured in isolated working control and hypertrophied rat hearts for 30 min before 20 min of global, no-flow ischemia and during 60 min of reperfusion. Selected control and hypertrophied hearts received 1.0 mmol/liter dichloroacetate (DCA), an activator of pyruvate dehydrogenase, at the time of reperfusion to stimulate glucose oxidation.
RESULTS
In the absence of DCA, glycolysis was higher and glucose oxidation and recovery of function were lower in hypertrophied hearts than in control hearts during reperfusion. Dichloroacetate stimulated glucose oxidation during reperfusion approximately twofold in both groups, while significantly reducing glycolysis in hypertrophied hearts. It also improved function of both hypertrophied and control hearts. In the presence of DCA, recovery of function of hypertrophied hearts was comparable to or better than that of untreated control hearts.
CONCLUSIONS
Dichloroacetate, given at the time of reperfusion, normalizes postischemic function of hypertrophied rat hearts and improves coupling between glucose oxidation and glycolysis by increasing glucose oxidation and decreasing glycolysis. These findings support the hypothesis that low glucose oxidation rates and high glycolytic rates contribute to the exaggerated postischemic dysfunction of hypertrophied hearts.
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Abbreviations and Acronyms
| | ANOVA | = analysis of variance | | ATP | = adenosine triphosphate | | DCA | = dichloroacetate | | NAD | = oxidized nicotinamide adenine dinucleotide | | NADH2 | = reduced nicotinamide adenine dinucleotide | | PDH | = pyruvate dehydrogenase | | PDK | = pyruvate dehydrogenase kinase | | pHi | = intracellular H+ concentration |
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