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EXPERIMENTAL STUDY

High levels of fatty acids delay the recoveryof intracellular pH and cardiac efficiency inpost-ischemic hearts by inhibiting glucose oxidation

Que Liu, MD^*, John C. Docherty, PhD, John C. T. Rendell, PhD, Alexander S. Clanachan, PhD^* and Gary D. Lopaschuk, PhD^*,*

^* Cardiovascular Research Group, University of Alberta, Edmonton, Canada
National Research Council, Institute for Biodiagnostics, Winnipeg, Canada

Manuscript received November 17, 2000; revised manuscript received November 5, 2001, accepted November 16, 2001.

^* Reprint requests and correspondence:Dr. Gary D. Lopaschuk, 423 Heritage Medical Research Building, The University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
gary.lopaschuk{at}ualberta.ca

OBJECTIVES: This study was designed to determine if the fatty acid-induced increase in H⁺ production from glycolysis uncoupled from glucose oxidation delays the recovery of intracellular pH (pH_i) during reperfusion of ischemic hearts.

BACKGROUND: High rates of fatty acid oxidation inhibit glucose oxidation and impair the recovery of mechanical function and cardiac efficiency during reperfusion of ischemic hearts.

METHODS: pH_i was measured by ³¹P nuclear magnetic resonance spectroscopy in isolated working rat hearts perfused in the absence (5.5 mmol/l glucose) or presence of 1.2 mmol/l palmitate (glucose+palmitate). Glycolysis and glucose oxidation were measured using [5-³H/U-¹⁴C]glucose.

RESULTS: When glucose+palmitate hearts were subjected to 20 min of no-flow ischemia, recoveries of mechanical function and cardiac efficiency were significantly impaired compared with glucose hearts. Glucose oxidation rates were significantly lower in glucose+palmitate hearts during reperfusion compared with glucose hearts, whereas glycolysis rates were unchanged. This resulted in an increase in H⁺ production from uncoupled glucose metabolism, and a decreased rate of recovery of pH_i in glucose+palmitate hearts during reperfusion compared with glucose-perfused hearts. Dichloroacetate (3 mmol/l) given at reperfusion to glucose+palmitate hearts resulted in a 3.2-fold increase in glucose oxidation, a 35% ± 3% decrease in H⁺ production from glucose metabolism, a 1.7-fold increase in cardiac efficiency and a 2.2-fold increase in the rate of pH_i recovery during reperfusion.

CONCLUSIONS: A high level of fatty acid delays the recovery of pH_i during reperfusion of ischemic hearts because of an increased H⁺ production from glycolysis uncoupled from glucose oxidation. Improving the coupling of glucose metabolism by stimulating glucose oxidation accelerates the recovery of pH_i and improves both mechanical function and cardiac efficiency.

Abbreviations and Acronyms   MVO2   ATP   adenosine triphosphate   DCA   dichloroacetate   ECLA   Estudios Cardiologicos Latinoamerica   GIK   glucose-insulin-potassium   MCT   lactate-H+ cotransporter   MVO2   myocardial oxygen consumption   NMR   nuclear magnetic resonance   PCr   phosphocreatine

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