Divergent Effects of Receptor- and Nonreceptor-Mediated Activators of Sodium-Hydrogen Exchange on Reperfusion-Induced Contractile Dysfunction

  • Morris Karmazyn
  • Nassirah Khandoudi
  • Josephine Ho
  • Christopher A. Ward
  • Margaret P. Moffat
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 168)


The regulation of intracellular pH in the cardiac cell is critical for the normal maintenance of cell function, particularly since protons are continuosly generated through various cellular processes. As changes in intracellular pH could profoundly affect cell function, the cardiac cell possesses numerous mechanisms for maintaining pH homeostasis. Among these, the sodium-hydrogen exchanger (NHE) plays an important role for pH regulation by extruding protons in exchange for sodium influx [1]. The exchanger is electroneutral, exchanging one H+ for one Na+. The acute regulation of NHE is under the control of various factors, although the pH gradient across the cardiac sarcolemma is likely the most critical. In addition, phosphorylation of the exchanger by protein kinase C (PKC) and other kinases results in the activation of the antiport. Thus, intracellular acidosis under conditions of normal extracellular pH represents a potent stimulus for NHE activation. In addition, direct activation of PKC or receptor-mediated stimulation of phosphoinositide hydrolysis, which results in increased production of diacylglycerol and subsequent PKC stimulation, both represent processes that result in NHE activation.


Phorbol Ester Positive Inotropic Effect Reperfused Myocardium Intracellular Acidosis Myocardial Reperfusion Injury 
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.
    Lazdunski M, Freiin 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 17:1029–1042.PubMedCrossRefGoogle Scholar
  2. 2.
    Rubanyi GM, Polokoff MA. 1994. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46:325–415.PubMedGoogle Scholar
  3. 3.
    Bogoyevitch MA, Parker PJ, Sugden PH. 1993. Characterization of protein kinase C isotype expression in adult rat heart. Protein kinase C epsilon is a major isotype present, and it is activated by phorbol esters, epinephrine, and endothelin. Cire Res 72:757–767.Google Scholar
  4. 4.
    Kramer BK, Smith TW, Kelly RA. 1991. Endothelin and increased contractility in adult rat ventricular myocytes. Role of intracellular alkalosis induced by activation of the protein kinase C-dependent Na+-H+ exchanger. Circ Res 68:269–279.PubMedGoogle Scholar
  5. 5.
    Khandoudi N, Ho J, Karmazyn M. 1994. Role of Na+-H+ exchange in mediating effects of endothelin-1 on normal and ischemic/reperfused hearts. Circ Res 75:369–378.PubMedGoogle Scholar
  6. 6.
    Iwakura K, Hori M, Watanabe Y, Kitabatake A, Cragoe EJ, Yoshida H, Kamada T. 1990. α1-Adrenoceptor stimulation increases intracellular pH and Ca2+ in cardiomyocytes through Na+/H+ and Na+/Ca2+ exchange. Eur J Pharmacol 186:29–40.PubMedCrossRefGoogle Scholar
  7. 7.
    Damron DS, Van Wagoner DR, Moravec CS, Bond M. 1993. Arachidonic acid and endothelin potentiate Ca2+ transients in rat cardiac myocytes via inhibition of distinct K+ channels. J Biol Chem 268:27335–27344.PubMedGoogle Scholar
  8. 8.
    Terzic A, Puceat M, Vassort G, Vogel SM. 1993. Cardiac α1-adrenoceptors: an overview. Pharmacol Rev 45:147–175.PubMedGoogle Scholar
  9. 9.
    Karmazyn M, Moffat MP. 1993. Role of Na+/H+ exchange in cardiac physiology and pathophysiology: mediation of myocardial reperfusion injury by the pH paradox. Cardiovasc Res 27:915–924.PubMedCrossRefGoogle Scholar
  10. 10.
    Murphy E, Perlman M, London RE, Steenbergen C. 1991. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res 68:1250–1258.PubMedGoogle Scholar
  11. 11.
    Ray SG, McMurray JJ, Morton JJ, Dargie HJ. 1992. Circulating endothelin in acute ischaemic syndromes. Br Heart J 67:383–386.PubMedCrossRefGoogle Scholar
  12. 12.
    Montalescot G, Viossat I, Chabrier PE, Sotirov I, Détienne JP, Drobinski G, Frank R, Grosgogeat Y, Thomas D. 1994. Endothelin-1 in patients with coronary heart disease undergoing cardiac catheterization. J Am Coll Cardiol 24:1236–1241.PubMedCrossRefGoogle Scholar
  13. 13.
    Lechleitner P, Genser N, Mair J, Maier J, Artner-Dworzak E, Dientsl F, Puschendorf B. 1993. Plasma immunoreactive endothelin in acute and subacute phases of myocardial infarction in patients undergoing fibrinolysis. Clin Chem 39:955–959.PubMedGoogle Scholar
  14. 14.
    Ameli S, Kaul S, Castro L, Arora C, Mirea A, Shah PK. 1993. Effect of percutaneous transluminal coronary angioplasty on circulating endothelin levels. Am J Cardiol 72: 1352–1356.PubMedCrossRefGoogle Scholar
  15. 15.
    Omland Y, Lie RT, Aakvaag A, Aaarsland T, Dickstein K. 1994. Plasma endothelin determination as a prognostic indicator of 1-year mortality after acute myocardial infarction. Circulation 89:1573–1579.PubMedGoogle Scholar
  16. 16.
    Watson JE, Karmazyn M. 1991. Concentration-dependent effects of protein kinase C-activating and -nonactivating phorbol esters on myocardial contractility, coronary resistance, energy metabolism, prostacyclin synthesis, and ultrastructure in isolated rat hearts. Effects of amiloride. Circ Res 69:1114–1131.PubMedGoogle Scholar
  17. 17.
    Hayashida W, Donckier J, Van Mechelen H, Stoleru L, Pouleur H. 1993. Endothelin-1 exacerbates diastolic stunning in conscious dogs. Am J Physiol 265:H1688–H1695.PubMedGoogle Scholar
  18. 18.
    Thandroyen FT, Worthington MG, Higginson LM, Opie LH. 1983. The effect of alpha-and beta-adrenoceptor antagonist agents on reperfusion ventricular fibrillation and metabolic status in the isolated perfused rat heart. J Am Coll Cardiol 1:1056–1066.PubMedCrossRefGoogle Scholar
  19. 19.
    Molina-Viamonte V, Anyukhovsky EP, Rosen MR. 1991. An α1-adrenergic receptor subtype is responsible for delayed afterdepolarizations and triggered activity during simulated ischemia and reperfusion of isolated canine Purkinje fibers. Circulation 84:1732–1740.PubMedGoogle Scholar
  20. 20.
    Sharma AD, Saffitz JE, Lee BI, Sobel BE, Corr PB. 1983. Alpha-adrenergic-mediated accumulation of calcium in reperfused myocardium. J Clin Invest 72:802–818.PubMedCrossRefGoogle Scholar
  21. 21.
    Corr PB, Heathers GP, Yamada KA. 1989. Mechanisms contributing to the arrhythmogenic influences of alpha1-adrenergic stimulation in the ischemic heart. Am J Med 87 (Suppl 2A):19S–25S.PubMedGoogle Scholar
  22. 22.
    Dillon JS, Gu XH, Nayler WG. 1988. Alpha1 adrenoceptors in the ischaemic and reperfused myocardium. J Mol Cell Cardiol 20:725–735.PubMedCrossRefGoogle Scholar
  23. 23.
    Khandoudi N, Moffat MP, Karmazyn M. 1994. Adenosine-sensitive α1-adrenoceptor effects on reperfused ischaemic hearts: comparison with phorbol ester. Br J Pharmacol 112: 1007–1016.PubMedGoogle Scholar
  24. 24.
    Kitakaze M, Hori M, Tamai J, Iwakura K, Koretsune Y, Kagiya T, Iwai K, Kitabatake A, Inoue M, Kamada T. 1987. α1-adrenoceptor activity regulates release of adenosine from the ischemic myocardium in dogs. Circ Res 60:631–639.PubMedGoogle Scholar
  25. 25.
    Ward CA, Moffat MP. 1995. Modulation of Na+/H+ exchange activity in cardiac myocytes during acidosis /realkalinization: effects on calcium, pHi and cell shortening. Cardio vase Res 29:247–253.Google Scholar
  26. 26.
    Rozanski GJ, Witt RC. 1994. Interleukin-1 enhances beta-responsiveness of cardiac L-type calcium current suppressed by acidosis. Am J Physiol 267:H1361–H1367.PubMedGoogle Scholar
  27. 27.
    Slater SJ, Kelly MB, Taddeo FJ, Rubin E, Stubbs CD. 1994. Evidence for discrete diacylg-lycerol and phorbol ester activator sites on protein kinase C. Differences in effects of 1-alkanol inhibition, activation by phosphatidylethanolamine and calcium chelation. J Biol Chem 269:17160–17165.PubMedGoogle Scholar
  28. 28.
    Bazzi MD, Nelsestuen GL. 1989. Properties of the protein kinase C-phorbol ester interaction. Biochemistry 28:3577–3585.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • Morris Karmazyn
  • Nassirah Khandoudi
  • Josephine Ho
  • Christopher A. Ward
  • Margaret P. Moffat

There are no affiliations available

Personalised recommendations