Basic Research in Cardiology

, Volume 91, Issue 3, pp 191–202 | Cite as

The role of Na+/H+ exchange in ischemia-reperfusion

  • H. M. Piper
  • C. Balser
  • Y. V. Ladilov
  • M. Schäfer
  • B. Siegmund
  • M. Ruiz-Meana
  • D. Garcia-Dorado
Original Contribution


In ischemia the cytosol of cardiomyocytes acidifies; this is reversed upon reperfusion. One of the major pHi-regulating transport systems involved is the Na+/H+ exchanger. Inhibitors of the Na+/H+ exchanger have been found to more effectively protect ischemic-reperfused myocardium when administered before and during ischemia than during reperfusion alone. It has been hypothesized that the protection provided by pre-ischemic administration is due to a reduction in Na+ and secondary Ca2+ influx. Under reperfusion conditions Na+/H+ exchange inhibition also seems protective since it prolongs intracellular acidosis which can prevent hypercontracture. In detail, however, the mechanisms by which Na+/H+ exchange inhibition provides protection in ischemic-reperfused myocardium are still not fully identified.

Key words

Acidosis calcium hypercontracture reperfusion injury Na+/HCO3 symporter 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Anderson SE, Murphy E, Steenbergen C, London RE, Cala PM (1990) Na+/H+ exchange in myocardium: effects of hypoxia and acidification on Na and Ca. Am J Physiol 259: C940-C948Google Scholar
  2. 2.
    Avkiran M, Ibuki C (1992) Reperfusion-induced arrhythmias. A role for washout of extracellular protons? Circ Res 71: 1429–1440Google Scholar
  3. 3.
    Balser C, Gögelein H, Scholz W, Albus U, Lang HJ, Russ U, Schölkens BA (1995) Interaction between intracellular calcium, sodium and protons in isolated rat cardiomyocytes. Europ J Physiol 429: R94 (abstract)Google Scholar
  4. 4.
    Bertrand B, Wakabayashi S, Ikeda T, Pouyssegur J, Shigekawa M (1994) The Na+/H+ exchange isoform 1 (NHE1) is a novel member of the calmodulin-binding proteins. Identification and characterization of calmodulin-binding sites. J Biol Chem 269: 13703–13709Google Scholar
  5. 5.
    Blank PS, Silverman HS, Chung OY, Hogue BA, Stern MD, Hansford RG, Lakatta EG, Capogrossi MC (1992) Cytosolic pH measurements in single cardiac myocytes using carboxy-seminaphthorhodafluor-1. Am J Physiol 263: H276-H284Google Scholar
  6. 6.
    Bond JM, Herman B, Lemasters JJ (1991) Protection by acidotic pH against anoxia/reoxygenation injury to rat neonatal cardiac myocytes. Biochem Biophys Res Commun 179: 798–803Google Scholar
  7. 7.
    Bugge E, Ytrehus K (1995) Inhibition of sodium-hydrogen exchange reduces infarct size in the isolated rat heart — a protective additive to ischaemic preconditioning. Cardiovasc Res 29: 269–274Google Scholar
  8. 8.
    Butwell NB, Ramasamy R, Lazar I, Sherry AD, Malloy CR (1993) Effect of lidocain on contracture, intracellular sodium and pH in ischemic rat hearts. Am J Physiol 264: H1884-H1889Google Scholar
  9. 9.
    Cala PM, Anderson SE, Cragoe EJ (1988) Na+/H+ exchange-dependent cell volume and pH regulation and disturbances. Comp Biochem Physiol 90a: 551–555Google Scholar
  10. 10.
    Carr P, Taub NA, Watts GF, Poston L (1993) Human lymphocyte sodium-hydrogen exchange. The influences of lipids, membrane fluidity, and insulin. Hypertension 21: 344–352Google Scholar
  11. 11.
    Clarke K, Stewart LC, Neubauer S, Balschi JA, Smith TW, Ingwall J (1993) Extracellular Volume and Transsar-colemmal movement during ischemia and reperfusion: a 31P NMR-spectroscopic study of the isovolumic rat heart. NMR in Biomedicine 6: 278–286Google Scholar
  12. 12.
    Counnillon L, Scholz W, Lang HJ, Pouyssegur J (1993) Pharmacological characterisation of stably transfected Na+/H+ exchangers isoforms using amiloride analogues and a new inhibitor possessing anti-ischemic properties. Mol Pharmacol 109: 562–568Google Scholar
  13. 13.
    De la Sierra A, Coca A, Paré JC, Sánchez M, Valls V, Urbano-Márquez A (1993) Erythrocyte ion fluxes in essential hypertensive patients with left ventricular hypertrophy. Circulation 88: 1628–1633Google Scholar
  14. 14.
    De Caterina M, Strazzullo P, Iacone R, Pompeo F, Varriale V, Grimaldi E, Scopacasa F (1994) Determination of the kinetics of Na+/H+ exchange in platelets using the Coulter S-plus cell counter. Eur J Clin Chem Clin Biochem 32: 57–60Google Scholar
  15. 15.
    Dennis SC, Coetzee WA, Cragoe EJ, Opie LH (1990) Effects of proton buffering and of amiloride derivates on reperfusion arrhythmias in isolated rat hearts. Possible evidence for an arrhythmogenic role of Na+/H+ exchange. Circ Res 66: 1156–1159Google Scholar
  16. 16.
    Dennis SC, Gevers W, Opie LH (1991) Protons in ischemia: Where do they come from; Where do they go to? J Mol Cell Cardiol 23: 1077–1086Google Scholar
  17. 17.
    Desilets M, Puceat M, Vassort G (1994) Chloride dependence of pH modulation by beta-adrenergic agonist in rat cardiomyocytes. Circ Res 75(5): 862–869Google Scholar
  18. 18.
    Duan J, Moffat MP (1992) Contractile and electrophysiologic effects of realkalization in cardiac tissues: role of Na+/H+ exchange and increased [Ca]i. Adv Exp Med Biol 311: 435–436Google Scholar
  19. 19.
    Duff HJ (1995) Clinical and in vivo antiarrhythmic potential of Na+/H+ exchange inhibitors. Cardiovasc Res 29: 1989–1993Google Scholar
  20. 20.
    Duff HJ, Mitchell LB, Kavanagh KM, Manyari DE, Gillis A, Wyse DG (1989) Amiloride: antiarrhythmic actions in patients with sustained ventricular tachycardia. Circulation 79: 1257–1263Google Scholar
  21. 21.
    Du Toit EF, Opie LH (1993) Role for the Na+/H+ exchanger in reperfusion stunning in isolated perfused rat heart. J Cardiovasc Pharmacol 22: 877–883Google Scholar
  22. 22.
    Dyck JRB, Lopaschuk GD, Fliegel L (1992) Identification of a small Na+/H+ exchanger-like message in the rabbit myocardium. FEBS Lett. 310: 255–259Google Scholar
  23. 23.
    Dyck JRB, Maddaford TG, Pierce GN, Fliegel L (1995) Induction of expression of the sodium-hydrogen exchanger in rat myocardium. Cardiovasc Res 29: 203–208Google Scholar
  24. 24.
    Ela C, Hasin Y, Eilam Y (1993) Opioid effects on contractility, Ca2+-transients and intracellular pH in cultured cardiac myocytes. J Mol Cell Cardiol 25: 599–613Google Scholar
  25. 25.
    Fliegel L, Dyck JRB (1995) Molecular Biology of the cardiac sodium-hydrogen exchanger. Cardiovasc Res 29: 155–159Google Scholar
  26. 26.
    Fliegel L, Fröhlich O (1993) The Na+/H+ exchanger: an update on structure, regulation and cardiac physiology. Biochem J 296: 273–285Google Scholar
  27. 27.
    Frelin C, Vigne P, Ladoux A, Lazdunski M (1988) The regulation of the intracellular pH in cells from vertebrates. Eur J Biochem 174: 3–14Google Scholar
  28. 28.
    Frelin C, Vigne P, Lazdunski M (1985) The role of Na+/H+ excchange system in the regulation of the internal pH in cultured cardiac cells. Eur J Biochem 149: 1–4Google Scholar
  29. 29.
    García ML, King VF, Shevell JL, Slaughter RS, Suarez-Kurtz G, Winquist RJ, Kaczorowski GJ (1990) Amiloride analogues inhibit L-type calcium channels and display calcium entry blocker activity. J Biol Chem 265: 3763–3771Google Scholar
  30. 30.
    García-Dorado D, González MA, Barrabés JA, Piper HM, Ruiz-Meana M, Solares J, Lidón RM, Blanco J, Puigfel Y, Soler-Soler J. Inhibition of Na+/H+ exchange during transient coronary occlusion and reperfusion (submitted)Google Scholar
  31. 31.
    García-Dorado D, Théroux P, Muñoz R et al. (1992) Favorable effects of hyperosmotic reperfusion on myocardial edema and infarct size. Am J Physiol 262: H17-H22Google Scholar
  32. 32.
    Gorgels APM, Vos MA, Lestch IS et al. (1988) Usefulness of the accelerated idioventricular rhythm as a marker of myocardial necrosis and reperfusion during thrombolytic therapy. Am J Cardiol 61: 231–235Google Scholar
  33. 33.
    Goss GG, Woodside M, Wakabayashi S, Pouyssegur J, Waddell T, Downey GP, Grinstein S (1994) ATP-dependence of NHE-1, the ubiquitous isoform of the Na+/H+ antiporter. Analysis of phosphorylation and subcellular localization. J Biol Chem 269: 8741–8748Google Scholar
  34. 34.
    Grinstein S, Woodside M, Sardet C, Pouyssegur J, Rotin D (1992) Activation of the Na+/H+ antiporter during cell volume regulation. Evidence for a phosphorylation-independent mechanism. J Biol Chem 267: 23823–23828Google Scholar
  35. 35.
    Grover AK, Samson SE (1993) Coronary artery acidosis: pH and calcium pump stability. Am J Physiol 265: H1486-H1492Google Scholar
  36. 36.
    Haigney MCP, Lakatta EG, Stern MD, Silverman HS (1994) Sodium Channel Blockade Reduces Hypoxic Sodium Loading and Sodium-Dependent-Calcium Loading. Circulation 90: 391–399Google Scholar
  37. 37.
    Harrison DC, Lemasters JJ, Herman B (1991) A pH-dependent phospholipase A2 contributes to loss of plasma membrane integrity during chemical hypoxia in rat hepatocytes. Biochem Biophys Res Commun 174: 654–659Google Scholar
  38. 38.
    Hendrikx M, Mubagwa K, Verdonck F, Overloop K, Van Hecke P, Vanstapel F, Van Lommel A, Verbeken E, Lauweryns J, Flameng W (1994) New Na+/H+ exchange inhibitor HOE 694 improves postischemic function, high-energy phosphate resynthesis and reduces Ca2+ overload in isolated perfused rabbit heart. Circ Res 89: 2787–2798Google Scholar
  39. 39.
    Kaplan SH, Yang H, Gilliam DE, Shen J, Lemasters JJ, Cascio WE (1995) Hypercapnic acidosis and dimethyl amiloride reduce reperfusion induced cell death in ischaemic ventricular myocardium. Cardiovasc Res 29: 231–238Google Scholar
  40. 40.
    Karmazyn M, Ray M, Haist JV (1993) Comparative effects of Na+/H+ exchanger inhibitors against cardiac injury produced by ischemia/reperfusion, hypoxia/reoxygenation and the Ca2+ paradox. J Cardiovasc Pharm 21: 172–178Google Scholar
  41. 41.
    Katoh H, Satoh H, Nakamura T, Terada H, Hayashi H (1994) The role of Na+/H+ exchange and the Na+/K+ pump in the regulation of [Na+]i during metabolic inhibition in guinea pig myocytes. Biochem Biophys Res Commun 203 (1): 93–98Google Scholar
  42. 42.
    Kimura M, Aviv A (1993) Regulation of the cytosolic pH set point for activation of the Na+/H+ antiport in human platelets: the role of the Na+/Ca2+ exchange, the Na+−K+−2Cl-cotransport and cellular volume. Pfluegers Arch 422: 585–590Google Scholar
  43. 43.
    Klein HH, Pich S, Bohle RM, Wollenweber J, Nebendahl K (1995) Myocardial Protection by Na+/H+ Exchange Inhibition in Ischemic Reperfused Porcine Hearts. Circulation 92: 912–917Google Scholar
  44. 44.
    Kleyman TR, Cragoe EJ (1988) Antiarr-rhythmic activity of amiloride: mechanisms. J Membr Biol 105: 1–21Google Scholar
  45. 45.
    Koop A, Piper HM (1992) Protection of energy status of hypoxic cardiomyocytes by mild acidosis. J Mol Cell Cardiol 24 (1): 55–65Google Scholar
  46. 46.
    Ladilov YV, Siegmund B, Piper HM (1995) Protection of reoxygenated cardiomyocytes against hypercontracture by inhibition of Na+/H+ exchange. Am J Physiol 268: H1531-H1539Google Scholar
  47. 47.
    Lagadic-Gossmann D, Buckler KJ, Vaughan-Jones RD (1992) Role of bicarbonate in-pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte. J Physiol (Lond) 458: 361–384Google Scholar
  48. 48.
    Lagadic-Gossmann D, Vaughan-Jones RD (1993) Coupling of dual acid extrusion in the guinea-pig isolated ventricular myocytes to α1 and β-adrenoreceptor. J Physiol 464: 49–73Google Scholar
  49. 49.
    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: 1029–1042Google Scholar
  50. 50.
    Little PJ, Neylon CB, Farrelly CA, Weissberg PL, Cragoe EJ, Bobik A (1995) Intracellular pH in vascular smooth muscle: Regulation by sodium-hydrogen exchange and multiple sodium dependent HCO3 mechanisms. Cardiovasc Res 29: 239–246Google Scholar
  51. 51.
    Meng HP, Maddaford TG, Pierce GN (1993) Effect of amiloride and selected analogues on postischemic recovery of cardiac contractile function. Am J Physiol 264: H1831-H1835Google Scholar
  52. 52.
    Meng HP, Pierce GN (1990) Protective effects of 5-(N,N-dimethyl)amiloride on ischemia-reperfusion injury in hearts. Am J Physiol 258: H1615-H1619Google Scholar
  53. 53.
    Mochizuki S, Seki S, Ejima M, Onodera T, Taniguchi M, Ishikawa S (1993) Na+/H+ exchange and reperfusion-induced ventricular arrhythmias in isolated perfused heart: possible role of amiloride. Mol Cell Biochem 119: 151–157Google Scholar
  54. 54.
    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: 959–971Google Scholar
  55. 55.
    Murphy E, Perlman M, London RE, Steenbergen C (1991) Amiloride delays the ischemia induced rise in cytosolic free calcium. Circ Res 68: 1250–1258Google Scholar
  56. 56.
    Myers ML, Mathur S, Li GH, Karmazyn M (1995) Sodium-hydrogen exchange inhibitors improve postischemic recovery of function in the perfused rabbit heart. Cardiovasc Res 29: 209–214Google Scholar
  57. 57.
    Navon G, Werrmann JG, Maron R, Cohen SM (1994) 31P NMR and triple quantum filtered 23Na NMR studies of the effects of inhibition of Na+/H+ exchange on intracellular sodium and pH in working and ischemic hearts. Magn Reson Med 32: 556–564Google Scholar
  58. 58.
    Orchard CH, Kentish JC (1990) Effects of changes of pH on the contractile function of cardiac muscle. Am J Physiol 258: C967-C981Google Scholar
  59. 59.
    Orlowski J, Kandasamy RA, Shull GE (1992) Molecular cloning of putative members of the Na+/H+ exchanger gene family. J Biol Chem 267: 9331–9339Google Scholar
  60. 60.
    Orlowski J (1993) Heterologous expression and functional properities of amiloride high affinity (NHE-1) and low affinity (NHE-3) isoforms of the Na+/H+ exchanger. J Biol Chem 268: 16369–16377Google Scholar
  61. 61.
    Periyasami SM (1992) Inhibition of cardiac sarcolemmal Na+/H+ antiporter by opioids. Can J Physiol Pharmacol 70: 1048–1056Google Scholar
  62. 62.
    Pierce GN, Cole WC, Liu K, Massaeli H, Maddaford TG, Chen YJ, McPherson CD, Jain S, Sontag D (1993) Modulation of cardiac performance by amiloride and several selected derivates of amiloride. J Pharmacol Exp Therap 265: 1280–1291Google Scholar
  63. 63.
    Pike MM, Luo CS, Clark MD, Kirk KA, Kitakaze M, Madden MC, Cragoe EJ Jr, Pohost GM (1993) NMR measurements of Na+ and cellular energy in ischemic rat heart: role of Na+/H+ exchange. Am J Physiol 265: H2017-H2026Google Scholar
  64. 64.
    Poch E, Botey A, Gaya J, Cases A, Rivera F, Revert L (1993) Intracellular calcium mobilization and activation on the Na+/H+ exchanger in platelets. Biochem J 290: 617–622Google Scholar
  65. 65.
    Puceat M, Clement-Chomienne O, Terzic A, Vassort G (1993) Alpha 1-adrenoceptor and purinoceptor agonists modulate Na+/H+ antiport in single cardiac cells. Am J Physiol 264: H310-H319Google Scholar
  66. 66.
    Puceat M, Vassort G (1995) Neurohumoral modulation of intracellular pH in the heart. Cardiovasc Res 29: 178–183Google Scholar
  67. 67.
    Reusch HP, Reusch R, Rosskopf D, Siffert W, Mann JF, Luft FC (1993) The Na+/H+ exchange in human lymphocytes and platelets in chronic and subacute metabolic acidosis. J Clin Invest 92: 858–865Google Scholar
  68. 68.
    Rosskopf D, Frömter E, Siffert W (1993) Hypertensive sodium-proton exchanger phenotype persists in immortalisized lymphoblasts from essential hypertensive patients. J Clin Invest 92 (5): 2553–2559Google Scholar
  69. 69.
    Ruiz-Meana M, García-Dorado D, Julià M, Inserte J, González MA, Barrabés JA, Soler-Soler J. Blockade of Na+/H+ exchange during metaboloc inhibition prevents reoxygenation-induced hypercontracture in isolated cardiomyocytes (submitted)Google Scholar
  70. 70.
    Ruiz-Meana M, García-Dorado D, González MA, Barrabés J, Soler-Soler J (1995) Effect of osmotic stress on sarcolemmal integrity of isolated myocytes following transient metabolic inhibition. Cardiovasc Res 30: 64–69Google Scholar
  71. 71.
    Sack S, Mohri M, Schwarz ER, Arras M, Schaper J, Ballagi-Pordány G, Scholz W, Lang HJ, Schölkens BA, Schaper W (1994) Effect of a new Na+/H+ antiporter inhibitor on postischemic reperfusion in pig heart. J Cardiovasc Pharmacol 23: 72–78Google Scholar
  72. 72.
    Sardet C, Fafournoux P, Pouyssegur J (1991) Alpha-thrombin, epidermal growth factor and okadaic acid activate the Na+/H+ exchanger, NHE-1; by phosphorylating a set of common site. J Biol Chem 266: 19166–19171Google Scholar
  73. 73.
    Schäfer M, Scholz W, Schölkens BA, Juretschke HP (1995) 31 P NMR studies on the influence of a new Na+/H+ exchange inhibitor (HOE 694) in a working rat heart system during ischemic and reperfusion. Pfluegers Arch 429, suppl: R97Google Scholar
  74. 74.
    Schlüter KD, Jakob G, Ruiz-Meana M, García-Dorado D, Piper HM (1996) Protection of reoxygenated cardiomyocytes against osmotic fragility by NO donors. Am J Physiol, in pressGoogle Scholar
  75. 75.
    Scholz W, Albus U, Lang HJ, Linz W, Martorana PA, Englert HC, Schölkens BA (1993) HOE 694, a new Na+/H+ exchange inhibitor and its effects in cardiac ischaemia. Brit J Pharmacol 109: 562–568Google Scholar
  76. 76.
    Scholz W, Albus U, Counillon L, Gögelein H, Lang HJ, Linz W, Weichert A, Schölkens BA (1995) Protective effects of HOE 642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res 29: 260–268Google Scholar
  77. 77.
    Scholz W, Albus U (1995) Potential of selective sodium-hydrogen exchange inhibitors in cardiovascular therapy. Cardiovasc Res 29: 184–188Google Scholar
  78. 78.
    Scholz W, Albus U (1993) Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion. Basic Res Cardiol 88: 443–455Google Scholar
  79. 79.
    Siczkowski M, Davies JE, Ng LL (1995) Sodium-hydrogen antiporter protein in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats. J Hypertens 12(7): 775–781Google Scholar
  80. 80.
    Siegmund B, Koop A, Klietz T, Schwartz P, Piper HM (1990) Sarcolemmal integrity and metabolic competence of cardiomyocytes under anoxia-reoxygenation. Am J Physiol 258: H285-H291Google Scholar
  81. 81.
    Siegmund B, Zude R, Piper HM (1992) Recovery of anoxic-reoxygenated cardiomyocytes from severe Ca2+-overload. Am J Physiol 263: H1262-H1269Google Scholar
  82. 82.
    Steenbergen C, Hill ML, Jennings RB (1985) Volume regulation and plasma membrane injury in aerobic, anaerobic and ischemic myocardium in vitro. Circ Res 57: 864–875Google Scholar
  83. 83.
    Takewaki S, Kuro-o M, Hiroi Y, yamazaki T, Noguchi T, Miyagishi A, Nakahara K, Aikawa M, Manabe I, Yazaki Y, Nagai R (1995) Activation of Na+/H+ antiporter (NHE-1) gene expression during growth, hypertrophy and proliferation of the rabbit cardiovascular system. J Mol Cell Cardiol 27: 729–742Google Scholar
  84. 84.
    Tani M, Neely JR (1989) Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+/Na+ and Na+/Ca2+ exchange. Circ Res 65: 1045–1056Google Scholar
  85. 85.
    Tomita M, Gotoh F (1992) Cascade of cell swelling: Thermodynamic potential discharge of brain cells after membrane injury. Am J Physiol 262: H603-H610Google Scholar
  86. 86.
    Vandenberg JI, Metcalfe JC, Grace AA (1993) Mechanisms of pHi recovery after global ischemia in the perfused heart. Circ Res 72: 993–1003Google Scholar
  87. 87.
    Verdonck F, Bielen FV, Ver Donck L (1991) Preferential block of the veratridine-induced, non-inactivating Na+ current by R56865 in single cardiac Purkinje cells. Eur J Pharmacol 203: 371–378Google Scholar
  88. 88.
    Wakabayashi S, Fafournoux P, Sardet C, Pouyssegur J (1992) The Na+/H+ antiporter cytoplasmic domain mediates growth factor signal and controls “H (+)-sensing”. Proc Natl Acad Sci USA 89: 2424–2428Google Scholar
  89. 89.
    Wallert MA, Fröhlich O (1989) Na+/H+ exchange in isolated myocytes from adult rat heart. Am J Physiol 257: C207-C213Google Scholar
  90. 90.
    Yasutake M, Avkiran M (1995) Exacerbation of reperfusion arrhythmias by alpha 1 adrenergic stimulation: a potential role for receptor mediated activation of sarcolemmal sodium-hydrogen exchange. Cardiovas Res 29: 222–230Google Scholar
  91. 91.
    Yasutake M, Ibuki C, Hearse DJ, Avkiran M (1994) Na+/H+ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor. Am J Phys 267: H2430-H2440Google Scholar

Copyright information

© Steinkopff Verlag 1996

Authors and Affiliations

  • H. M. Piper
    • 1
  • C. Balser
    • 1
  • Y. V. Ladilov
    • 1
  • M. Schäfer
    • 1
  • B. Siegmund
    • 1
  • M. Ruiz-Meana
    • 2
  • D. Garcia-Dorado
    • 2
  1. 1.Physiologisches Institut der Justus-Liebig-UniversitätGießenFRG
  2. 2.Servicio de CardiologiaHospital General Vall d'HebronBarcelonaSpain

Personalised recommendations