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© 1999 American Heart Association, Inc.
Reviews |
The Myocardial Na+-H+ Exchange
Structure, Regulation, and Its Role in Heart Disease
From the Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario, Canada.
Correspondence to Dr Morris Karmazyn, Department of Pharmacology and Toxicology, Medical Sciences Bldg, University of Western Ontario, London, Ontario N6A 5C1, Canada. E-mail mkarm{at}julian.uwo.ca
Abstract—The Na+-H+ exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion. There are at least 6 NHE isoforms thus far identified with the NHE1 subtype representing the major one found in the mammalian myocardium. This 110-kDa glycoprotein extrudes protons concomitantly with Na+ influx in a 1:1 stoichiometric relationship rendering the process electroneutral, and its activity is regulated by numerous factors, including phosphorylation-dependent processes. There is convincing evidence that NHE mediates tissue injury during ischemia and reperfusion, which probably reflects the fact that under conditions of tissue stress, including ischemia, Na+-K+ ATPase is inhibited, thereby limiting Na+ extrusion, resulting in an elevation in [Na+]i. The latter effect, in turn, will increase [Ca2+]i via Na+-Ca2+ exchange. In addition, NHE1 mRNA expression is elevated in response to injury, which may further contribute to the deleterious consequence of pathological insult. Extensive studies using NHE inhibitors have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and has led to clinical evaluation of NHE inhibition in patients with coronary artery disease. Emerging evidence also implicates NHE1 in other cardiac disease states, and the exchanger may be particularly critical to postinfarction remodeling responses resulting in development of hypertrophy and heart failure.
Key Words: Na+-H+ exchange • ischemia/reperfusion • remodeling • hypertrophy • heart failure
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D. R. Knight, A. H. Smith, D. M. Flynn, J. T. MacAndrew, S. S. Ellery, J. X. Kong, R. B. Marala, R. T. Wester, A. Guzman-Perez, R. J. Hill, et al. A Novel Sodium-Hydrogen Exchanger Isoform-1 Inhibitor, Zoniporide, Reduces Ischemic Myocardial Injury in Vitro and in Vivo J. Pharmacol. Exp. Ther., April 1, 2001; 297(1): 254 - 259. [Abstract] [Full Text]
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M. Avkiran, G. Gross, M. Karmazyn, H. Klein, E. Murphy, and K. Ytrehus Na+/H+ exchange in ischemia, reperfusion and preconditioning Cardiovasc Res, April 1, 2001; 50(1): 162 - 163. [Full Text] [PDF]
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D. G Allen and X.-h. Xiao Na+ entry during ischemia, reperfusion and preconditioning Cardiovasc Res, April 1, 2001; 50(1): 164 - 166. [Full Text] [PDF]
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R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 15, 2001; (2001) 51599198. [Abstract] [Full Text]
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K. Kusumoto, J. V. Haist, and M. Karmazyn Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H738 - H745. [Abstract] [Full Text] [PDF]
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X-H. Xiao and D.G. Allen Activity of the Na+/H+ exchanger is critical to reperfusion damage and preconditioning in the isolated rat heart Cardiovasc Res, November 1, 2000; 48(2): 244 - 253. [Abstract] [Full Text] [PDF]
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H. Yokoyama, S. Gunasegaram, S. E. Harding, and M. Avkiran Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium J. Am. Coll. Cardiol., August 1, 2000; 36(2): 534 - 540. [Abstract] [Full Text] [PDF]
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C. Ruwhof and A. van der Laarse Mechanical stress-induced cardiac hypertrophy: mechanisms and signal transduction pathways Cardiovasc Res, July 1, 2000; 47(1): 23 - 37. [Abstract] [Full Text] [PDF]
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H. Yoshida and M. Karmazyn Na+/H+ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium Am J Physiol Heart Circ Physiol, January 1, 2000; 278(1): H300 - H304. [Abstract] [Full Text] [PDF]
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A. N. Moor, X. T. Gan, M. Karmazyn, and L. Fliegel Activation of Na+/H+ Exchanger-directed Protein Kinases in the Ischemic and Ischemic-reperfused Rat Myocardium J. Biol. Chem., May 4, 2001; 276(19): 16113 - 16122. [Abstract] [Full Text] [PDF]
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R. B. Silver, C. J. Mackins, N. C. E. Smith, I. L. Koritchneva, K. Lefkowitz, T. W. Lovenberg, and R. Levi Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia PNAS, February 27, 2001; 98(5): 2855 - 2859. [Abstract] [Full Text] [PDF]
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K. Imahashi, T. Nishimura, J. Yoshioka, and H. Kusuoka Role of Intracellular Na+ Kinetics in Preconditioned Rat Heart Circ. Res., June 8, 2001; 88(11): 1176 - 1182. [Abstract] [Full Text] [PDF]
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M. G. Vila Petroff, J. M. Egan, X. Wang, and S. J. Sollott Glucagon-Like Peptide-1 Increases cAMP but Fails to Augment Contraction in Adult Rat Cardiac Myocytes Circ. Res., August 31, 2001; 89(5): 445 - 452. [Abstract] [Full Text] [PDF]
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B. V. Alvarez, J. Fujinaga, and J. R. Casey Molecular Basis for Angiotensin II-Induced Increase of Chloride/Bicarbonate Exchange in the Myocardium Circ. Res., December 7, 2001; 89(12): 1246 - 1253. [Abstract] [Full Text] [PDF]
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S. Engelhardt, L. Hein, U. Keller, K. Klambt, and M. J. Lohse Inhibition of Na+-H+ Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in {beta}1-Adrenergic Receptor Transgenic Mice Circ. Res., April 19, 2002; 90(7): 814 - 819. [Abstract] [Full Text] [PDF]
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