Receptor-Mediated Regulation of the Cardiac Sarcolemmal Na+/H+ Exchanger

Mechanisms And (Patho)Physiological Significance
  • Robert S. Haworth
  • Metin Avkiran


Intracellular pH (pHi) homeostasis in cardiac myocytes is achieved principally by the integrated action of 4 different sarcolemmal ion transporters (1). When the myocyte cytoplasm becomes acidic, the Na+/H+ exchanger (NHE) and the Na+/HCO3 - cotransporter (NBC) extrude acid from the cell, while under conditions of intracellular alkalosis, the Cl-/HCO3 - and Cl-/OH- exchangers effectively import acid. In order to investigate the function and regulation of NHE, experimental protocols are often performed in the absence of bicarbonate, which renders NBC inactive and thereby makes NHE the sole acid extrusion pathway. NHE activity is regulated primarily by pHi, and increases markedly in response to intracellular acidosis (1) through the interaction of H+ with an allosteric modifier site on the transport domain (2,3). The basal activity of the sarcolemmal NHE is low under physiological conditions, while increasing intracellular acidosis leads to a pHi-dependent increase in NHE activity, with a Hill coefficient of around 3 (4). This indicates that more than 1 proton binds to the NHE protein during the transport cycle, and has led to the suggestion that the NHE protein contains a non-transporting proton-binding site which allosterically modifies NHE activity. Thus, as pHi falls, the proton modifier site becomes increasingly occupied, leading to a greater increase in NHE activity than would be expected by simply in creasing the availability of transportable protons.


Ventricular Myocytes Positive Inotropic Effect Purkinje Fibre Thrombin Receptor Rabbit Ventricular Myocytes 
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  1. 1.
    Leem, CH, Lagadic-Gossman, D, Vaughan-Jones, RD. Characterisation of intracellular pH regulation in the guinea-pig ventricular myocyte. J Physiol 517.1:159–180, 1999PubMedCrossRefGoogle Scholar
  2. 2.
    Wakabayashi, S, Bertrand, B, Shigekawa, M, Fafournoux, P, Pouyssegur, J. Growth factor activation and “H+-sensing” of the Na+/H+ exchanger isoform 1 (NHE-1). J Biol Chem 269: 5583–5588, 1994PubMedGoogle Scholar
  3. 3.
    Wakabayashi, S, Bkeda, T, Iwamoto, T, Pouyssegur, J, Shigekawa, M. Calmodulin-binding autoinhibitory domain controls “pH-sensing” in the Na+/H+ exchanger NHE1 through sequence-specific interaction. Biochemistry 36:12854–12861, 1997PubMedCrossRefGoogle Scholar
  4. 4.
    Wallert, MA, Frohlich, O. Na+/H+ exchange in isolated myocytes from adult rat heart. Am J Physiol 257: C207–C213, 1989PubMedGoogle Scholar
  5. 5.
    Fliegel, L, Dyck, JRB, Wang, H, Fong, C, Haworth, RS. Cloning and analysis of the human myocardial Na+/H+ exchanger. Mol Cell Biochem 125:137–143, 1993PubMedCrossRefGoogle Scholar
  6. 6.
    Petrecca, K, Atanasiu, R, Grinstein, S, Orlowski, J, Shrier A. Subcellular localization of the Na+/H+ exchanger NHE1 in rat myocardium. Am J Physiol 276: H709–H717, 1999PubMedGoogle Scholar
  7. 7.
    Wakabayashi, S, Fafournoux, P, Sardet, C, Pouysségur, J. The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls “FT-sensing”. Proc Natl Acad Sci 89:2424–2428, 1992PubMedCrossRefGoogle Scholar
  8. 8.
    Sardet, C, Counillon, L, Franchi, A, Pouysségur, J. Growth factors induce phosphorylation of the Na+/H+ antiporter, a glycoprotein of 110 kDa. Science 247:723–726, 1990PubMedCrossRefGoogle Scholar
  9. 9.
    Sardet, C, Fafournoux, P, Pouysségur, J.α-thrombin, EGF and okadaic acid activate the Na+/H+ exchanger, NHE1 by phosphorylating a set of common sites. J Biol Chem 266: 19166–19171, 1991PubMedGoogle Scholar
  10. 10.
    Fliegel, L, Walsh, MP, Singh, D, Wong, C, Barr, A. Phosphorylation of the C-terminal domain of the Na+/H+ exchanger by Ca2+/calmodulin-dependent protein kinase n. Biochem J 282:139–145, 1992PubMedGoogle Scholar
  11. 11.
    Wang, H, Silva, NLCL, Lucchesi, PA, Haworth, R, Wang, K, Michalak, M, Pelech, S, Fliegel, L. Phosphorylation and regulation of the Na+/H+ exchanger through mitogen-activated protein kinase. Biochemistry 36:9151–9158, 1997PubMedCrossRefGoogle Scholar
  12. 12.
    Takahashi, E, Abe, J, Gallis, B, Aebersold, R, Spring,DJ, Krebs, EG, Berk, BC. p90rsk is a serum-stimulated Na+/H+ exchanger isoform-1 kinase: regulatory phosphorylation of serine 703 of Na+/H+ exchanger isoform-1. J Biol Chem 274:20206–20214, 1999PubMedCrossRefGoogle Scholar
  13. 13.
    Khaled, AR, Moor, AN, Li, A, Kim, K, Ferris, DK, Muegge, K, Fisher, RJ, Fliegel, L, Durum, SK. Trophic factor withdrawl: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization. Mol Cell Biol 21:7545–7557, 2001PubMedCrossRefGoogle Scholar
  14. 14.
    Yan, W, Nehrke, K, Choi, J, Barber, DL. The Nck-interacting kinase (NIK) phosphorylates the Na+-H+ exchanger NHE1 and regulates NHE1 activation by platelet-derived growth factor. J Biol Chem 276: 31349–31356, 2001PubMedCrossRefGoogle Scholar
  15. 15.
    Winkel, GK, Sardet, C, Pouyssegur, J, Ives, HE. Role of cytoplasmic domain of the Na+/H+ exchanger in hormonal activation. J Biol Chem 268: 3396–3400, 1993PubMedGoogle Scholar
  16. 16.
    Bertrand, B, Wakabayashi, S, Dceda, T, Pouyssegur, J, Shigekawa, M. The Na+/H+ exchanger isoform 1 (NHE-1) is a novel member of the calmodulin binding proteins. J Biol Chem 269:13703–13709, 1994PubMedGoogle Scholar
  17. 17.
    Wakabayashi, S, Bertrand, B, Dceda, T, Pouyssegur, J, Shigekawa, M. Mutation of calmodulin-binding site renders the Na+/H+ exchanger (NHE1) highly tf-sensitive and Ca2+ regulation-defective. J Biol Chem 269:13710–13715, 1994PubMedGoogle Scholar
  18. 18.
    Lin, X, Barber, DL. A calcineurin homologous protein inhibits GTPase-stimulated Na+/H+ exchange. Proc Natl Acad Sci 93:12631–12636, 1996PubMedCrossRefGoogle Scholar
  19. 19.
    Pang, T, Su, X, Wakabayashi, S, Shigekawa, M. Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers. J Biol Chem 276:17367–17372, 2001PubMedCrossRefGoogle Scholar
  20. 20.
    Iwakura, K, Hori, M, Watanabe, Y, Kitabatake, A, Cragoe, EJ, Yoshida, H, Kamada, T. α1-Adrenoceptor stimulation increases intracellular pH and Ca2+ in cardiomyocytes through Na+/H+ and Na+/Ca2+ exchange. Eur J Pharmacol 186:29–40, 1990PubMedCrossRefGoogle Scholar
  21. 21.
    Terzic, A, Puceat, M, Clement, O, Scamps, F, Vassort, G. α1-Adrenergic effects on intracellular pH and calcium and on myofilaments in single rat cardiac cells. J Physiol 447:275–292, 1992PubMedGoogle Scholar
  22. 22.
    Wallert, MA, Frdhlich, O. α1-Adrenergic stimulation of Na+-H+ exchange in cardiac myocytes. Am J Physiol 263: C1096–C1102, 1992PubMedGoogle Scholar
  23. 23.
    Lagadic-Gossmann, D, Vaughan-Jones, RD. Coupling of dual acid extrusion in the guinea-pig isolated ventricular myocyte to alpha 1- and beta-adrenoceptors. J Physiol 464:49–73, 1993PubMedGoogle Scholar
  24. 24.
    Scofield, MA, Liu, F, Abel, PW, Jeffries,WB. Quantification of steady state expression of mRNA for alpha-1 adrenergic receptor subtypes using reverse transcription and a competitive polymerase chain reaction. J Pharmacol Expt Therapeut 275: 1035–1042, 1995Google Scholar
  25. 25.
    Yokoyama, H, Yasutake, M, Avkiran, M. arAdrenergic stimulation of sarcolemmal Na+/H+ exchanger activity in rat ventricular myocytes: evidence for selective mediation by the a,A-adrenoceptor subtype. Circ Res 82:1078–1085, 1998PubMedCrossRefGoogle Scholar
  26. 26.
    Snabaitis, AK, Yokoyama, H, Avkiran, M. Roles of mitogen-activated protein kinases and protein kinase C in D 1A-adrenoceptor-mediated stimulation of the sarcolemmal Na+/H+ exchanger. Circ Res 86:214–220, 2000PubMedCrossRefGoogle Scholar
  27. 27.
    Guo, H, Wasserstrom, JA, Rosenthal, JE. Effect of catecholamines on intracellular pH in sheep cardiac Purkinje fibres. J Physiol 458:289–306, 1992PubMedGoogle Scholar
  28. 28.
    Wu, ML, Tseng, YZ. The modulatory effects of endothelin-1, carbachol and isoprenaline upon Na+/H+ exchange in dog cardiac Purkinje fibres. J Physiol 471: 583–597, 1993PubMedGoogle Scholar
  29. 29.
    Wu, ML, Vaughan-Jones, RD. Effect of metabolic inhibitors and second messengers upon Na+-H+ exchange in the sheep Purkinje fibre. J Physiol 478: 301–313, 1994PubMedGoogle Scholar
  30. 30.
    Wakabayashi, S, Shigekawa, M, Pouysségur, J. Molecular physiology of vertebrate Na+/H+ exchangers. Physiol Rev 77: 51–74, 1997PubMedGoogle Scholar
  31. 31.
    Kaibara, M, Mitarai, S, Yano, K, Kameyama, M. Involvement of Na+-H+ antiporter in regulation of L-type Ca2+ channel current by angiotensin II in rabbit ventricular myocytes. Circ. Res. 75:1121–1125, 1994Google Scholar
  32. 32.
    Grace, AA, Metcalfe, JC, Weissberg, PL, Bethell, HWL, Vandenberg, JI. Angiotensin II stimulates sodium-dependent proton extrusion in perfused ferret heart. Am J Physiol 270: C1687–C1694, 1996PubMedGoogle Scholar
  33. 33.
    Ito, N, Kagaya, Y, Weinberg, EO, Barry, WH, Lorell, BH. Endothelin and angiotensin II stimulation of Na+/H+ exchange is impaired in cardiac hypertrophy. J Clin Invest 99: 125–135, 1997PubMedCrossRefGoogle Scholar
  34. 34.
    Gunasegaram, S, Haworth, RS, Hearse, DJ, Avkiran, M. Regulation of sarcolemmal Na+/H+ exchanger activity by angiotensin II in adult rat ventricular myocytes. Circ Res 85:919–930, 1999PubMedCrossRefGoogle Scholar
  35. 35.
    Krämer, BK, Smith, TW, Kelly, RA. Endothelin and increased contractility in adult rat ventricular myocytes. Circ Res 68:269–279, 1991PubMedCrossRefGoogle Scholar
  36. 36.
    Brunner, F, Opie, LH. Role of endothelin-A receptors in ischemic contracture and reperfusion injury. Circulation 97:391–398, 1998PubMedCrossRefGoogle Scholar
  37. 37.
    Fareh, J, Touyz, RM, Schiffiin, EL, Thibault, G. Endothelin-1 and angiotensin II receptors in cells from rat hypertrophied heart. Receptor regulation and intracellular Ca2+ modulation. Circ Res 78:302–311, 1996PubMedCrossRefGoogle Scholar
  38. 38.
    Coughlin, SR. Thrombin receptor function and cardiovascular disease. Trends Cardiovasc Med 4:77–83, 1994PubMedCrossRefGoogle Scholar
  39. 39.
    Yasutake, M, Haworth, RS, King, A, Avkiran, M. Thrombin activates the sarcolemmal Na+/H+ exchanger: evidence for a receptor-mediated mechanism involving protein kinase C. Circ Res 79:705–715, 1996PubMedCrossRefGoogle Scholar
  40. 40.
    Vu, TKH, Hung, DT, Wheaton, VI, Coughlin, SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057–1068, 1991PubMedCrossRefGoogle Scholar
  41. 41.
    Connolly, AJ, Ishihara, H, Kahn, ML, Farese, RV, Coughlin, SR. Role of the thrombin receptor in development and evidence for a second receptor. Nature 381:516–519,1996PubMedCrossRefGoogle Scholar
  42. 42.
    Ishihara, H, Connolly, AJ, Zeng, D, Kahn, ML, Zheng, YW, Timmons, C, Tram, T, Coughlin, SR. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386:502–506, 1997PubMedCrossRefGoogle Scholar
  43. 43.
    Sabri, A, Muske, G, Zhang, H, Pak, E, Darrow, A, Andrade-Gordon, P, Steinberg, SF. Signaling properties and functions of two distinct cardiomyocyte protease-activated receptors. Circ Res 86:1054–1061, 2000PubMedCrossRefGoogle Scholar
  44. 44.
    Avkiran, M, Yokoyama, H. Adenosine A1 receptor stimulation inhibits α1-adrenergic activation of the cardiac sarcolemmal Na+/H+ exchanger. Brit J Pharmacol 131: 659–662, 2000.CrossRefGoogle Scholar
  45. 45.
    Dhein, S, van Koppen, CJ, Brodde, OE. Muscarinic receptors in the mammalian heart. Pharmacol Res 44:161–182, 2001PubMedCrossRefGoogle Scholar
  46. 46.
    Szokodi, I, Tavi, P, Foldes, G, Voutilainen-Myllyla, S, lives, M, Tokola, H, Pikkarainen, S, Piuhola, J, Toth, M, Ruskoaho, H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res 91:434–440, 2002PubMedCrossRefGoogle Scholar
  47. 47.
    Baetz, D, Haworth, RS, Avkiran, M, Feuvray, D. The ERK pathway regulates Na+-HCO3 - cotransport activity in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 283: H2102–H2109, 2002PubMedGoogle Scholar
  48. 48.
    Desilets, M, Puceat, M, Vassort, G. Chloride dependence of pH modulation by β-adrenergic agonists in rat cardiomyocytes. Circ Res 75: 862–869, 1994PubMedCrossRefGoogle Scholar
  49. 49.
    Camilion de Hurtado, MC, Alvarez, BV, Ennis, IL, Cingolani, HE. Stimulation of myocardial Na+-independent C1--HCO3 - exchanger by angiotensin II is mediated by endogenous endothelin. Circ Res 86:622–627, 2000CrossRefGoogle Scholar
  50. 50.
    Orchard, CH, Kentish, JC. Effects of changes of pH on the contractile function of cardiac muscle. Am J Physiol 258: C967–C981, 1990PubMedGoogle Scholar
  51. 51.
    Despa, S, Islam, MA, Pogwizd, SM, Bers, DM. Intracellular [Na+] and Na+ pump rate in rat and rabbit ventricular myocytes. J Physiol 539: 133–143, 2002PubMedCrossRefGoogle Scholar
  52. 52.
    Gambassi, G, Spurgeon, HA, Lakatta, EG, Blank, PS, Capogossi, MC. Different effects of α- and β-adrenergic stimulation on cytosolic pH and myofilament responsiveness to Ca2+ in cardiac myocytes. Circ Res 71: 870–882, 1992PubMedCrossRefGoogle Scholar
  53. 53.
    Matsui, H, Barry, WH, Livsey, C, Spitzer, KW. Angiotensin D stimulates sodium-hydrogen exchange in adult rabbit ventricular myocytes. Cardiovasc Res 29: 215–221, 1995PubMedGoogle Scholar
  54. 54.
    Fujii, N, Tanaka, M, Ohnishi, J, Yukawa, K, Takimoto, E, Shimada, S, Naruse, M, Sugiyama, F, Yagami, K, Murakami, K, Miyazaki, H. Alterations of angiotensin II receptor contents in hypertrophied hearts. Biochem Biophys Res Commun 212: 326–333, 1995PubMedCrossRefGoogle Scholar
  55. 55.
    Wang, H, Sakurai, K, Endoh, M. Pharmacological analysis by HOE642 and KB-R9032 of the role of Na+/H+ exchange in the endothelin-1-induced Ca2+ signalling in rabbit ventricular myocytes. Br. J. Pharmacol. 131: 638–644, 2000PubMedCrossRefGoogle Scholar
  56. 56.
    Hoque, N, Cook, MA, Karmazyn, M. Inhibition of α1-adrenergic-mediated responses in rat ventricular myocytes by adenosine A1 receptor activation: role of the KATP channel. J. Pharmacol. Exp. Ther. 294: 770–777, 2000PubMedGoogle Scholar
  57. 57.
    Alvarez, BV, Pérez, NG, Ennis, IL, Camilion de Hurtado, MC, Cingolani HE. Mechanisms underlying the increase in force and Ca2+ transient that follow stretch of cardiac muscle: a possible explanation of the Anrep effect. Circ Res 85: 716–722, 1999PubMedCrossRefGoogle Scholar
  58. 58.
    Pérez, NG, de Hurtado, MC, Cingolani, HE. Reverse mode of the Na+-Ca2+ exchange after myocardial stretch: underlying mechanism of the slow force response. Circ Res 88:376–382, 2001PubMedCrossRefGoogle Scholar
  59. 59.
    Avkiran, M. Sodium-hydrogen exchange in myocardial ischemia and reperfusion: a critical determinant of injury? In Myocardial ischemia: mechanisms, reperfusion, protection. M. Karmazyn, editor. Birkhauser Verlag, Basel. 299–311. 1996.CrossRefGoogle Scholar
  60. 60.
    Avkiran, M. Protection of the ischaemic myocardium by Na+/H+ exchange inhibitors: potential mechanisms of action. Basic Res. Cardiol. 96: 306–311, 2001Google Scholar
  61. 61.
    Avkiran, M. Rational basis for use of sodium-hydrogen exhange inhibitors in myocardial ischemia. Am J Cardiol 83:10G–18G, 1999PubMedCrossRefGoogle Scholar
  62. 62.
    Karmazyn, M, Gan, XT, Humphreys, RA, Yoshida, H, Kusumoto, K. The myocardial Na+-H+ exchange: structure, regulation, and its role in heart disease. Circ Res 85:777–786, 1999PubMedCrossRefGoogle Scholar
  63. 63.
    Théroux, P, Chaitman, BR, Danchin, N, Erhardt, LRW, Meinertz, T, Schroder, JS, Tognoni, G, White, HD, Willerson, JT, Jessel, A. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations: main results of the GUARDIAN trial. Circulation 102:3032–3038, 2000PubMedCrossRefGoogle Scholar
  64. 64.
    Avkiran, M, Marber, MS. Na+/H+ exchange inhibitors for cardioprotective therapy: progress, problems and prospects. J Am Coll Cardiol 39:747–753, 2002PubMedCrossRefGoogle Scholar
  65. 65.
    Schomig, A, Richardt, G. Cardiac sympathetic activity in myocardial ischemia: release and effects of noradrenaline. Basic Res Cardiol 85:9–30, 1990PubMedCrossRefGoogle Scholar
  66. 66.
    Corr, PB, Yamada, KA, DaTorre, SD. Modulation of α-adrenergic receptors and their intracellular coupling in the ischemic heart. Basic Res Cardiol 85:31–45, 1990PubMedGoogle Scholar
  67. 67.
    Pucéat, M, Cement-Chomienne, O, Terzic, A, Vassort, G.α1-adrenoceptor and purinoceptor agonists modulate Na-H antiport in single cardiac cells. Am J Physiol 264: H310–H319, 1993PubMedGoogle Scholar
  68. 68.
    Khandoudi, N, Moffat, MP, Karmazyn, M. Adenosine-sensitive α1-adrenoceptor effects on reperfused ischaemic hearts: comparison with phorbol ester. Br J Pharmacol 112: 1007–1016, 1994PubMedCrossRefGoogle Scholar
  69. 69.
    Yasutake, M, Ibuki, C, Hearse, DJ, Avkiran, M. Na+/H+ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor. Am J Physiol 267: H2430–H2440, 1994PubMedGoogle Scholar
  70. 70.
    Yasutake, M, Avkiran, M. Exacerbation of reperfusion arrhythmias by α1-adrenergic stimulation: a potential role for receptor-mediated activation of sarcolemmal sodium-hydrogen exchange. Cardiovasc Res 29:222–230, 1995PubMedGoogle Scholar
  71. 71.
    Davies, MJ, Woolf, N, Robertson, WB. Pathology of acute myocardial infarction with particular reference to occlusive coronary thrombi. Br Heart J 38:659–664, 1976PubMedCrossRefGoogle Scholar
  72. 72.
    Wagner, WR, Hubbell, JA. Local thrombin synthesis and fibrin formation in an in vitro thrombosis model result in platelet recruitment and thrombin stabilization on collagen in heparinized blood. J Lab Clin Med 116:636–650, 1990PubMedGoogle Scholar
  73. 73.
    Yan, GX, Park, TH, Corr, PB. Activation of thrombin receptor increases intracellular Na+ during myocardial ischemia. Am. J. Physiol. 268: H1740–H1748, 1995.PubMedGoogle Scholar
  74. 74.
    Yokoyama, H, Avkiran, M. Protein kinase C-mediated stimulation of the sarcolemmal Na+/H+ exchanger contributes to the arrhythmogenic action of thrombin (abstr.). Circulation 96:158, 1997Google Scholar
  75. 75.
    Tonnessen, T, Naess, PA, Kirkboen, KA, Offstad, J, Ilebekk, A, Christensen G. Endothelin is released from the porcine coronary circulation after short-term ischemia. J. Cardiovasc. Pharmacol. 22: S313–S316, 1993PubMedCrossRefGoogle Scholar
  76. 76.
    Khandoudi, N, Ho, J, Karmazyn, M. Role of Na+-H+ exchange in mediating effects of endothelin-1 on normal and ischemic/reperfused hearts. Circ. Res. 75:369–378, 1994Google Scholar
  77. 77.
    Yang, Z, Cerniway, RJ, Byford,AM, Berr, SS, French, BA, Matherne, GP. Cardiac overexpression of A1-adenosine receptor protects intact mice against myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 282: H949–H955, 2002PubMedGoogle Scholar
  78. 78.
    Dorn, GW, Brown, JH. Gq signaling in cardiac adaptation and maladaptation. Trends Cardiovasc. Med. 9:26–34, 1999Google Scholar
  79. 79.
    Ito, H, Hirata, Y, Adachi, S, Tanaka, M, Tsujino, M, Koike, A, Nogami, A, Murumo, F, Hiroe, M. Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin H-induced hypertrophy in cultured rat cardiomyocytes. J. Clin. Invest. 92:398–403, 1993PubMedCrossRefGoogle Scholar
  80. 80.
    Glembotski, CC, Irons, CE, Krown, KA, Murray, SF, Sprenkle, AB, Sei, CA. Myocardial □-thrombin receptor activation induces hypertrophy and increases atrial natriuretic factor gene expression. J. Biol. Chem. 268:20646–20652, 1993PubMedGoogle Scholar
  81. 81.
    Knowlton, KU, Michel, MC, Itani, M, Shubeita, HE, Ishihara, K, Brown, JH, Chien, KR. The α1A-adrenergic receptor subtype mediates biochemical, molecular, and morphologic features of cultured myocardial cell hypertrophy. J. Biol. Chem. 268: 15374–15380, 1993PubMedGoogle Scholar
  82. 82.
    Sadoshima, J, Izumo, S. Molecular characterisation of angiotensin II-induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ. Res. 73:413–423, 1993Google Scholar
  83. 83.
    Schluter, KD, Schafer, M, Balser, C, Taimor, G, Piper, HM. Influence of pHi and creatine phosphate on α-adrenoceptor-mediated cardiac hypertrophy. J. Mol. Cell Cardiol. 30: 763–771, 1998PubMedCrossRefGoogle Scholar
  84. 84.
    Schafer, M, Schafer, C, Piper, HM, Schluter, KD. Hypertrophic responsiveness of cardiomyocytes to α- or β-adrenoceptor stimulation requires sodium-proton-exchanger-1 (NHE-1) activation but not cellular alkalinization. Eur. J. Heart Fail. 4:249–254, 2002PubMedCrossRefGoogle Scholar
  85. 85.
    Engelhardt, S, Hein, L, Keller, U, Klambt, K, Lohse, MJ. Inhibition of Na+-H+ exchange prevents hypertrophy, fibrosis, and heart failure in β1-adrenergic receptor transgenic mice. Circ. Res. 90: 814–819, 2002Google Scholar
  86. 86.
    Yamazaki, T, Komuro, I, Kudoh, S, Zou, Y, Nagai, R, Aikawa, R, Uozumi, H, Yazaki, Y. Role of ion channels and exchangers in mechanical stretch-induced cardiomyocyte hypertrophy. Circ. Res. 82:430–437, 1998Google Scholar
  87. 87.
    Hasegawa, S, Nakano, M, Taniguchi, Y, Imai, S, Murata, K, Suzuki, T. Effects of Na+-H+ exchange blocker amiloride on left ventricular remodeling after anterior myocardial infarction in rats. Cardiovasc. Drug Ther. 9: 823–826, 1995Google Scholar
  88. 88.
    Yoshida, H, Karmazyn, M. Na+/H+ exchange inhibition attenuates hypertrophy and heart failure in 1-wk postinfarction rat myocardium. Am. J. Physiol. Heart Circ. Physiol. 278: H300–H304, 2000PubMedGoogle Scholar
  89. 89.
    Spitznagel, H, Chung, O, Xia, QG, Rossius, B, Illner, S, Jähnichen, G, Sandmann, S, Reinecke, A, Daemen MJAP, Unger T. Cardioprotective effects of the Na+/H+ -exchange inhibitor cariporide in infarct-induced heart failure. Cardiovasc. Res. 46:102–110, 2000Google Scholar
  90. 90.
    Kusumoto, K, Haist, JV, Karmazyn, M. Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am. J. Physiol. 280: H738–H745, 2001Google Scholar
  91. 91.
    Camilion de Hurtado, MC, Portiansky, EL, Perez, NG, Rebolledo, OR, Cingolani, HE. Regression of cardiomyocyte hypertrophy in SHR following chronic inhibition of the Na+/H+ exchanger. Cardiovasc. Res. 53: 862–868, 2002Google Scholar
  92. 92.
    Chen, L, Gan, XT, Haist, JV, Feng, Q, Lu X, Chakrabarti, S, Karmazyn, M. Attenuation of compensatory right ventricular hypertrophy and heart failure following monocrotaline-induced pulmonary vascular injury by the Na+-H+ exchange inhibitor cariporide. J. Pharmacol. Exp. Ther. 298:469–476, 2001PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Robert S. Haworth
    • 1
  • Metin Avkiran
    • 1
  1. 1.Centre for Cardiovascular Biology and Medicine, King’s College London, The Rayne InstituteSt Thomas’ HospitalLondonUK

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