Cardiac-Specific Ablation of the Na -Ca Exchanger Confers Protection Against Ischemia/Reperfusion Injury

During ischemia and reperfusion, with an increase in intracellular Na and a depolarized membrane potential, Ca may enter the myocyte in exchange for intracellular Na via reverse-mode Na -Ca exchange (NCX). To test the role of Ca entry via NCX during ischemia and reperfusion, we studied mice with cardiac-specific ablation of NCX (NCX-KO) and demonstrated that reverse-mode Ca influx is absent in the NCX-KO myocytes. Langendorff perfused hearts were subjected to 20 minutes of global ischemia followed by 2 hours of reperfusion, during which time we monitored high-energy phosphates using P-NMR and left-ventricular developed pressure. In another group of hearts, we monitored intracellular Na using Na-NMR. Consistent with Ca entry via NCX during ischemia, we found that hearts lacking NCX exhibited less of a decline in ATP during ischemia, delayed ischemic contracture, and reduced maximum contracture. Furthermore, on reperfusion following ischemia, NCX-KO hearts had much less necrosis, better recovery of left-ventricular developed pressure, improved phosphocreatine recovery, and reduced Na overload. The improved recovery of function following ischemia in NCX-KO hearts was not attributable to the reduced preischemic contractility in NCX-KO hearts, because when the preischemic workload was matched by treatment with isoproterenol, NCX-KO hearts still exhibited improved postischemic function compared with wild-type hearts. Thus, NCX-KO hearts were significantly protected against ischemia-reperfusion injury, suggesting that Ca entry via reverse-mode NCX is a major cause of ischemia/reperfusion injury. (Circ Res. 2005;97:916-921.)