Metabolic inhibition in the perfused rat heart: evidence for glycolytic requirement for normal sodium homeostasis

Subcellular compartmentalization of energy stores to support different myocardial processes has been exemplified by the glycolytic control of the ATP-sensitive K+ channel. Recent data suggest that the control of intracellular sodium (Na-i) may also rely on glycolytically derived ATP; however, the degree of this dependence is unclear. To examine this question, isolated, perfused rat hearts were exposed to hypoxia, to selectively inhibit oxidative metabolism, or iodoacetate (IAA, 100 mu mol/l), to selectively inhibit glycolysis. Na-i and myocardial high-energy phosphate levels were monitored using triple-quantum-filtered (TQF) Na-23 and P-31 magnetic resonance spectroscopy, respectively. The effects of ion exchange mechanisms (Na+/Ca2+, Na+/H+) on Na-i were examined by pharmacological manipulation of these channels. Na-i, as monitored by shift reagent-aided TQF Na-23 spectral amplitudes, increased by similar to 220% relative to baseline after 45 min of perfusion with IAA, with or without rapid pacing. During hypoxia, Na-i increased by similar to 200% during rapid pacing but did not increase in unpaced hearts or when the Na+/H+ exchange blocker ethylisopropylamiloride (EIPA, 10 mu mol/l) was used. Neither EIPA nor a low-Ca2+ perfusate (50 mu mol/l) could prevent the rise in Na-i during perfusion with IAA. Myocardial function and high-energy phosphate stores were preserved during inhibition of glycolysis with IAA and continued oxidative metabolism. These results suggest that glycolysis is required for normal Na+ homeostasis in the perfused rat heart, possibly because of preferential fueling of Na-K-adenosinetriphosphatase by glycolytically derived ATP.