Possible Pathway of Na<sup>+</sup> Flux into Mitochondria in Ischemic Heart

Abstract

Previous studies showed that myocardial Na(+) overload during ischemia directly induced mitochondrial damage. The pathway for Na(+) flux into mitochondria remains unclear. We examined possible routes for Na(+) flux into mitochondria in the ischemic heart. Isolated perfused rat hearts were subjected to 15- to 35-min ischemia followed by 60-min reperfusion and then Na(+) content and respiratory function in mitochondria of the ischemic heart were determined. The mitochondrial Na(+) content of the ischemic heart was ischemic duration-dependently increased, associated with a reduction in mitochondrial respiratory function. To mimic induction of mitochondrial Na(+) overload in vitro, isolated mitochondria were incubated with 6.25 to 50 mM NaCl or sodium lactate, a metabolite of anaerobic glycolysis, in the presence and absence of a mitochondrial Na(+)/Ca(2+) exchanger inhibitor CGP37157 and a monocarboxylate transporter (MCT) inhibitor α-cyano-4-hydroxy cinnamic acid (CHCA). Incubation of mitochondria with NaCl or sodium lactate increased the mitochondrial Na(+) concentration. This increase in mitochondrial Na(+) was partially attenuated by the presence of either inhibitor. Combined treatment of mitochondria with both inhibitors attenuated sodium lactate-induced increase in Na(+) content to a greater degree than that treated with either agent. These results suggest that mitochondrial Na(+)/Ca(2+) exchanger and MCT inhibitor-sensitive Na(+) transporter are possible pathways for the mitochondrial Na(+) overload in the ischemic myocardium.