Inhibition of the Sarcolemmal Sodium-Hydrogen Exchanger: A Potential Treatment for Resuscitation from Cardiac Arrest

  • R. J. Gazmuri
  • I. M. Ayoub
  • J. Kolarova
Conference paper


Increased sarcolemmal sodium (Na+) influx with subsequent intracellular Na+ overload due to inability of the Na+-K+ pump to extrude Na+ has been recognized as an important pathogenic mechanism of cell injury during ischemia and reperfusion [1–5]. Na+ becomes a ‘substrate’ for reperfusion injury [6] and intensifies processes detrimental to cell function (see below). The principal routes for Na+ entry are the sarcolemmal sodium-hydrogen exchanger isoform-1 (NHE-1), the Na+-HCO 3 co-transporter, and Na+ channels. However, under conditions of ischemia and reperfusion, NHE-1 seems to be the predominant route.


Cardiac Arrest Ventricular Fibrillation Chest Compression Myocardial Stunning Monophasic Action Potential 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Karmazyn M (1988) Amiloride enhances postischemic ventricular recovery: Possible role of Na+/H+ exchange. Am J Physiol 255: H608–H615PubMedGoogle Scholar
  2. 2.
    Lazdunski M, Frelin C, Vigne P (1985) The sodium/hydrogen exchange system in cardiac cells: its biochemical and pharmacological properties and its role in regulating internal concentrations of sodium and internal pH. J Mol Cell Cardiol 17: 1029–1042PubMedCrossRefGoogle Scholar
  3. 3.
    Moffat MP, Karmazyn M (1993) Protective effects of the potent Na/H exchange inhibitor methylisobutyl amiloride against post-ischemic contractile dysfunction in rat and guinea-pig hearts. J Mol Cell Cardiol 25: 959–971PubMedCrossRefGoogle Scholar
  4. 4.
    Bersohn MM (1995) Sodium pump inhibition in sarcolemma from ischemic hearts. J Mol Cell Cardiol 27: 1483–1489PubMedCrossRefGoogle Scholar
  5. 5.
    Avkiran M (1999) Rational basis for use of sodium-hydrogen exchange inhibitors in myocardial ischemia. Am J Cardiol 83: 10G–17GPubMedCrossRefGoogle Scholar
  6. 6.
    Imahashi K, Kusuoka H, Hashimoto K, Yoshioka J, Yamaguchi H, Nishimura T (1999) Intracellular sodium accumulation during ischemia as the substrate for reperfusion injury. Circ Res 84: 1401–1406PubMedCrossRefGoogle Scholar
  7. 7.
    Gazmuri RJ, Hoffner E, Kalcheim J, et al (2001) Myocardial protection during ventricular fibrillation by reduction of proton-driven sarcolemmal sodium influx. J Lab Clin Med 137: 43–55PubMedCrossRefGoogle Scholar
  8. 8.
    Gazmuri RJ, Ayoub IM, Hoffner E, Kolarova JD (2001) Successful ventricular defibrillation by the selective sodium-hydrogen exchanger isoform-1 inhibitor cariporide. Circulation 104: 234–239PubMedCrossRefGoogle Scholar
  9. 9.
    Gazmuri RJ, Ayoub IM, Kolarova JD, Karmazyn M (2002) Myocardial protection during ventricular fibrillation by inhibition of the sodium-hydrogen exchanger isoform-1. Crit Care Med 30: S166–S171PubMedCrossRefGoogle Scholar
  10. 10.
    Rupprecht HJ, vom DJ, Terres W, et al (2000) Cardioprotective effects of the Na(+)/H(+) exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA. Circulation 101: 2902–2908PubMedCrossRefGoogle Scholar
  11. 11.
    Theroux P, Chaitman BR, Danchin N, et al (2000) Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators. Circulation 102: 3032–3038PubMedCrossRefGoogle Scholar
  12. 12.
    Yokoyama H, Gunasegaram S, Harding SE, Avkiran M (2000) Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium. J Am Coll Cardiol 36: 534–540PubMedCrossRefGoogle Scholar
  13. 13.
    Karmazyn M, Gan XT, Humphreys RA, Yoshida H, Kusumoto K (1999) The myocardial Na(+)-H(+) exchange: structure, regulation, and its role in heart disease. Circ Res 85: 777–786PubMedCrossRefGoogle Scholar
  14. 14.
    Karmazyn M, Sostaric JV, Gan XT (2001) The myocardial Na+/H+ exchanger: a potential therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and attenuation of postinfarction heart failure. Drugs 61: 375–389PubMedCrossRefGoogle Scholar
  15. 15.
    Mosca SM, Cingolani HE (2000) Comparison of the protective effects of ischemic preconditioning and the Na+/H+ exchanger blockade. Naunyn Schmiedebergs Arch Pharmacol 362: 7–13PubMedCrossRefGoogle Scholar
  16. 16.
    An J, Varadarajan SG, Camara A, et al (2001) Blocking Na(+)/H(+) exchange reduces [Na(+)](1) and [Ca(2+)](1) load after ischemia and improves function in intact hearts. Am J Physiol 281: H2398–H2409Google Scholar
  17. 17.
    Mosca SM, Cingolani HE (2001) [The Na+/Ca2+ exchanger as responsible for myocardial stunning]. Medicina (B Aires) 61: 167–173PubMedGoogle Scholar
  18. 18.
    Halestrap AP, McStay GP, Clarke SJ (2002) The permeability transition pore complex: another view. Biochimie 84: 153–166PubMedCrossRefGoogle Scholar
  19. 19.
    Kitakaze M, Weisfeldt ML, Marban E (1988) Acidosis during early reperfusion prevents myocardial stunning in perfused ferret hearts. J Clin Invest 82: 920–927PubMedCrossRefGoogle Scholar
  20. 20.
    Scholz W, Albus U, Counillon L, et al (1995) Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 29: 260–268PubMedGoogle Scholar
  21. 21.
    Ditchey RV, Horwitz LD (1985) Metabolic evidence of inadequate coronary blood flow during closed-chest resuscitation in dogs. Cardiovasc Res 19: 419–425PubMedCrossRefGoogle Scholar
  22. 22.
    Ditchey RV, Goto Y, Lindenfeld J (1992) Myocardial oxygen requirements during experimental cardiopulmonary resuscitation. Cardiovasc Res 26: 791–797PubMedCrossRefGoogle Scholar
  23. 23.
    Gazmuri RJ, Berkowitz M, Cajigas H (1999) Myocardial effects of ventricular fibrillation in the isolated rat heart. Crit Care Med 27: 1542–1550PubMedCrossRefGoogle Scholar
  24. 24.
    Downey J (1976) Compression of the coronary arteries by the fibrillating heart. Circ Res 39: 53–57PubMedCrossRefGoogle Scholar
  25. 25.
    Koretsune Y, Marban E (1990) Mechanism of ischemic contracture in ferret hearts: Relative roles of [Ca2+]; elevation and ATP depletion. Am J Physiol 258: H9–H16PubMedGoogle Scholar
  26. 26.
    Klouche K, Weil MH, Sun S, et al (2002) Evolution of the stone heart after prolonged cardiac arrest. Chest 122: 1006–1011PubMedCrossRefGoogle Scholar
  27. 27.
    Takino M, Okada Y (1996) Firm myocardium in cardiopulmonary resuscitation. Resuscitation 33: 101–106PubMedCrossRefGoogle Scholar
  28. 28.
    Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG (2000) Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 343: 1206–1209PubMedCrossRefGoogle Scholar
  29. 29.
    Caffrey SL, Willoughby PJ, Pepe PE, Becker LB (2002) Public use of automated external defibrillators. N Engl J Med 347: 1242–1247PubMedCrossRefGoogle Scholar
  30. 30.
    Niemann JT, Cairns CB, Sharma J, Lewis RJ (1992) Treatment of prolonged ventricular fibrillation. Immediate countershock versus high-dose epinephrine and CPR preceding countershock. Circulation 85: 281–287PubMedCrossRefGoogle Scholar
  31. 31.
    Cobb LA, Fahrenbruch CE, Walsh TR, et al (1999) Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 281: 1182–1188PubMedCrossRefGoogle Scholar
  32. 32.
    Kolarova JD, Ayoub IM, Yi Z, Gazmuri RJ. (2003) Optimal timing for electrical defibrillation after prolonged untreated ventricular fibrillation. Crit Care Med. (In press)Google Scholar
  33. 33.
    Kellermann AL, Hackman BB, Somes (1993) Predicting the outcome of unsuccessful pre-hospital advanced cardiac life support. JAMA 270: 1433–1436PubMedCrossRefGoogle Scholar
  34. 34.
    Franz MR (2000) Monophasic action potentials recorded by contact electrode method. Genesis, measurement, and interpretations. In: Franz MR (ed) Monophasic Action Potentials. Bridging Cell and Bedside. Futura Publishing Company, Armonk, pp 19–45Google Scholar
  35. 35.
    Wirth KJ, Uhde J, Rosenstein B, et al (2000) KvTP channel blocker HMR 1883 reduces monophasic action potential shortening during coronary ischemia in anesthetised pigs. Naunyn Schmiedebergs Arch Pharmacol 361: 155–160PubMedCrossRefGoogle Scholar
  36. 36.
    Wirth KJ, Maier T, Busch AE (2001) NHEI-inhibitor cariporide prevents the transient reperfusion-induced shortening of the monophasic action potential after coronary ischemia in pigs. Basic Res Cardiol 96: 192–197PubMedCrossRefGoogle Scholar
  37. 37.
    Gazmuri RJ, Weil MH, Bisera J, Tang W, Fukui M, McKee D (1996) Myocardial dysfunction after successful resuscitation from cardiac arrest. Crit Care Med 24: 992–1000PubMedCrossRefGoogle Scholar
  38. 38.
    Kern KB, Hilwig RW, Rhee KH, Berg RA (1996) Myocardial dysfunction after resuscitation from cardiac arrest: An example of global myocardial stunning. J Am Coll Cardiol 28: 232–240PubMedCrossRefGoogle Scholar
  39. 39.
    Mullner M, Domanovits H, Sterz F, et al (1998) Measurement of myocardial contractility following successful resuscitation: quantitated left ventricular systolic function utilising non-invasive wall stress analysis. Resuscitation 39: 51–59PubMedCrossRefGoogle Scholar
  40. 40.
    Karmazyn M (1999) Mechanisms of protection of the ischemic and reperfused myocardium by sodium-hydrogen exchange inhibition. J Thromb Thrombolysis 8: 33–38PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • R. J. Gazmuri
  • I. M. Ayoub
  • J. Kolarova

There are no affiliations available

Personalised recommendations