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(Circulation Research. 2005;97:916.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Cardiac-Specific Ablation of the Na⁺-Ca²⁺ Exchanger Confers Protection Against Ischemia/Reperfusion Injury

Kenichi Imahashi, Christian Pott, Joshua I. Goldhaber, Charles Steenbergen, Kenneth D. Philipson, Elizabeth Murphy

From the Laboratory of Signal Transduction (K.I., E.M.), National Institute of Environmental Health Sciences, Research Triangle Park, NC; Departments of Physiology and Medicine, The Cardiovascular Research Laboratories (C.P., J.I.G., K.D.P.), David Geffen School of Medicine, University of California at Los Angeles; and Department of Pathology (C.S.), Duke University Medical Center, Durham, NC.

Correspondence to Elizabeth Murphy, Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709. E-mail murphy1{at}niehs.nih.gov

During ischemia and reperfusion, with an increase in intracellular Na⁺ and a depolarized membrane potential, Ca²⁺ may enter the myocyte in exchange for intracellular Na⁺ via reverse-mode Na⁺-Ca²⁺ exchange (NCX). To test the role of Ca²⁺ entry via NCX during ischemia and reperfusion, we studied mice with cardiac-specific ablation of NCX (NCX-KO) and demonstrated that reverse-mode Ca²⁺ 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 ³¹P-NMR and left-ventricular developed pressure. In another group of hearts, we monitored intracellular Na⁺ using ²³Na-NMR. Consistent with Ca²⁺ 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 Ca²⁺ entry via reverse-mode NCX is a major cause of ischemia/reperfusion injury.

Key Words: Na⁺-Ca²⁺ exchange • genetically altered mice • ischemia/reperfusion injury

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