Summary
The characterization of various ion transport systems has led to a better understanding of the effects, which seem to take part in the impairment of ischemic and reperfused cardiac tissue. This review discusses the role of the Na+/H+ exchange system in the pathophysiology of ischemia and reperfusion and the beneficial effects of its inhibition.
At the onset of ischemia intracellular pH (pHi) decreases due to anaerobic metabolism and ATP hydrolysis, leading to an activation of Na+/H+ exchange. This in turn increases intracellular Na+ (Na+ i) and activates Na+/K+ ATPase, with a consecutive increase of energy consumption. Since cellular Na+ and Ca++ transport are coupled by the Na+/Ca++ exchange system, which depends on the Na+ gradient, the high Na+ i leads to increased intracellular Ca++ (Ca++ i). After a certain period, Na+/H+ exchange is inactivated by a decrease of extracellular pH.
In case of reperfusion the acid extracellular fluid is washed out, which reactivates Na+/H+ exchange, leading to an unfavourably fast restoration of pHi and a second time to Na+ and Ca++ i overflow.
High Ca++ i is assumed to be one of the main reasons for ischemic and reperfusion injury, like arrhythmias, myocardial contracture, stunning and necrosis.
It seems that the inhibition of Na+/H+ exchange can interrupt this process at an early phase and prevent or delay the consequences of ischemia and reperfusion as demonstrated by numerous investigators.
Similar content being viewed by others
References
Allen DG, Orchard CH (1987) Myocardial contractile function during ischemia and hypoxia. Circulat Res 60:153–168
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-C948
Aronson PS (1985) Kinetic properties of the plasma membrane Na+/H+-exchanger. Ann Rev Physiol 47:545–560
Avkiran M, Ibuki C (1992) Reperfusion-induced arrhythmias — a role for washout of extracellular protons? Circulat Res 71:1429–1440
Barry WH, Peeters GA, Rasmussen CAF, Cunningham MJ (1987) Role of changes in [Ca++]i in energy deprivation contracture. Circulat Res 61:726–734
Beers MF, Carty SE, Johnson RG, Scarpa A (1982) H+-ATPase and catecholamine transport in chromaffin granules. Ann NY Acad Sci 402:116–133
Beuckelmann DJ, Wier WG (1989) Sodium-calcium exchange in guinea-pig cardic cells: Exchange current and changes in intracellular Ca++. J Physiol 414:499–520
Blanchard EM, Solaro RJ (1984) Inhibition of the activation and troponin calcium binding of dog cardiac myofibrils by acidic pH. Circulat Res 55:382–391
Borgers M, Piper HM (1986) Calcium shifts in anoxic cardiac myocytes: A cytochemical study. J Mol Cell Cardiol 18:439–448
Camacho SA, Lanzer P, Toy J, Gober J, Valenza M, Botvinick EH, Weiner MW (1988) In vivo alterations of high-energy phosphates and intracellular pH during reversible ischemia in pigs: A 31P magnetic resonance spectroscopy study. Amer Heart J 116:701–708
Cingolani HE, Mattiazzi AR, Blesa ES, Conzalez HE (1970) Contractility in isolated mammalia heart muscle after acid-base changes. Circulat Res 26:269–278
Cobbe SM, Poole-Wilson PA (1980) Tissue acidosis in myocardial hypoxia. J Mol Cell Cardiol 12:761–770
Cobbe SM, Poole-Wilson PA (1980) The time of onset and severity of acidosis in myocardial ischaemia. J Mol Cell Cardiol 12:745–760
Coetzee WA, Opie LH (1987) Effects of components of ischemia and metabolic inhibition on delayed afterdepolarizations in guinea pig papillary muscle. Circulat Res 61:157–165
Corr PB, Gillis RA (1978) Autonomic neutral influences on the dysrhythmias resulting from myocardial infarction. Circulat Res 43:1–9
Dennis SC, Coetzee WA, Cragoe EJ, Opie LH (1990) Effects of proton buffering and of amiloride derivatives on reperfusion arrhythmias in isolated rat hearts. Circulat Res 66:1156–1159
Dennis SC, Gevers W, Opie LH (1991) Protons in ischemia: Where do they come from; Where do they go to? J Mol Cell Cardiol 23:1077–1086
Duan J, Karmazyn M (1992) Protective effects of amiloride on the ischemic reperfused rat heart. Relation to mitochondrial function. Europ J Pharmacol 210:149–157
Duff HJ, Lester WM, Rahmberg M (1988) Amiloride, antiarrhythmic and electrophysiological activity in the dog. Circulation 78:1469–1477
Elliot AC, Smith GL, Eisner DA, Allen DG (1992) Metabolic changes during ischaemia and their role in contractile failure in isolated ferret hearts. J Physiol 454:467–490
Ellis D, MacLeod KT (1985) Sodium-dependent control of intracellular pH in Purkinje fibers of sheep heart. J Physiol 359:81–105
Fabiato A, Fabiato F (1978) Effects of pH on the myofilaments and the sarcoplasmic reticulum of skinned cells from cardiac and skeletal muscle. J Physiol 276:233–255
Fralix TA, Murphy E, London RE, Steenbergen C (1993) Protective effects of adenosine in the perfused rat heart: changes in metabolism and intracellular ion homeostasis. Am J Physiol 264:C986-C994
Fralix TA, Steenbergen C, London RE, Murphy E (1993) Glibenclamide does not abolish the protective effect of preconditioning on stunning in the isolated perfused rat heart. Cardiovasc Res 27:630–637
Frelin C, Vigne P, Lazdunski M (1984) The role of Na+/H+ exchange system in cardiac cells in relation to the control of the internal Na+ concentration. J Biol Chem 259:8880–8885
Frelin C, Vigne P, Lazdunski M (1985) The role of Na+/H+ exchange system in the regulation of the internal pH in cultured cardiac cells. Eur J Biochem 149:1–4
Garlick PB, Radda GK, Seeley PJ (1979) Studies of acidosis in the ischemic heart by phosphorus nuclear magnetic resonance. Biochem J 184:547–554
Glitsch HG (1982) Electrogenic Na pumping in the heart. Ann Rev Physiol 44:389–400
Gudbjarnason S, Mathes P, Ravens KG (1970) Functional compartmentation of ATP and creatine phosphate in heart muscle. J Mol Cell Cardiol 1:325–339
Haigney MCP, Miyata H, Lakatta EG, Stern MD, Silverman HS (1992) Dependence of hypoxic cellular calcium loading on Na+−Ca++ exchange. Circulat Res 71:547–557
Harrison SM, Frampton JE, McCall E, Boyett MR, Orchard CH (1992) Contraction and intracellular Ca++, Na+, and H+ during acidosis in rat ventricular myocytes. Am J Physiol 262:C348-C357
Hearse DJ, Humphrey SM, Bullock GR (1978) The oxygen paradox and the calcium paradox: two facets of the same problem? J Mol Cell Cardiol 10:641–668
Hendrikx M, Mubagwa K, Flameng W (1993) Inhibition of Na+/H+ exchange protects against postischemic dysfunction in isolated, blood perfused rabbit heart. J Mol Cell Cardiol 25:VI P 12 (Abstract)
Imai S, Shi AY, Ishibashi T, Nakazawa M (1991) Na+/H+ exchange is not operative under low flow ischemic conditions. J Mol Cell Cardiol 23:505–517
Ishibashi T, Nakazawa M, Imai S (1993) Ischemic changes in myocardial ionic contents of the isolated perfused rat heart as studies by NMR. Molec Cell Biochem 119:109–120
Jungermann K, Möhler H (1980) Biochemie. Springer-Verlag, Berlin Heidelberg New York pp 165–167
Kaila K, Vaughan-Jones RD (1987) Influence of sodium-hydrogen exchange on intracellular pH, sodium and tension in sheep cardiac Purkinje fibers. J Physiol 390:93–118
Karmazyn M (1988) Amiloride enhances postischemic ventricular recovery: possible role of Na+/H+ exchange. Am J Physiol 255:H608-h615
Kazumasa H, Franklin A, Johnson RG, Grossman W, Morgan JP (1992) Na+/H+; Na+/Ca+ exchange enhance and ATP-sensitive K+ channels ameliorate cell Ca++ rise in ischemia. Circulation 86:1903 (Abstract)
Kentish JC, Nayler WG (1979) The influence of pH on the Ca2+-regulated ATPase of cardiac and white skeletal myofibrils. J Mol Cell Cardiol 11:611–617
Kimura J, Noma A, Irisawa H (1986) Na−Ca exchange current in mammalian heart cells. Nature 319:596–597
Kitakaze M, Weisfeldt ML, Marban E (1988) Acidosis during early reperfusion prevents myocardial stunning in perfused ferret hearts. J Clin Invest 82:920–927
Kleber AG (1983) Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischemia in isolated perfused guinea pig hearts. Circulat Res 52:442–450
Kleyman TR, Cragoe EJ (1988) Antiarrhythmic activity of amiloride: mechanisms. J Membr Biol 105:1–21
Kutryk MJB, Dhalla NS (1988) Alterations in cardiac lysosomal hydrolases following induction of the calcium paradox. Can J Physiol Pharmacol 65/11:2175–2181
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 17:1029–1042
Lederer WJ, Niggli E, Hadley RW (1990) Sodium-calcium exchange in excitable cells. Fuzzy space. Science 248:283
MacLeod KT (1989) Effects of hypoxia and metabolic inhibition on the intracellular sodium activity of mammalian ventricular muscle. J Physiol 416:455–468
Malliani A, Schwartz PJ, Zanchetti A (1980) Neural mechanisms in life-threatening arrhythmias. Amer Heart J 100:705–715
Malloy CR, Buster DC, Margarida M, Castro M, Geraldes CFGC, Jeffrey FMH, Sherry AD (1990) Influence of global ischemia on intracellular sodium in the perfused rat heart. Magn Reson Med 15:33–44
Maron R (1989) Functional and metabolic protection by Na+/H+ exchange inhibition in global ischemia. J Mol Cell Cardiol 21:1226 (Abstract)
Mattiazzi AR, Cingolani HE (1977) Biphasic effect of hypercapnia on myocardial contractility. Arch Int Phys Biochem 85:11–25
Mattiazzi AR, Cingolani HE, Spacapan de Castuma E (1979) Relationship between calcium and hydrogen ions in heart muscle. Am J Physiol 237:H497-H503
Meng HP, Lonsberry BB, Pierce GN (1991) Influence of perfusate pH on the postischemic recovery of cardiac contractile function: Involvement of sodium-hydrogen exchange. J Pharmacol Exp Ther 258:772–777
Miura Y, Kimura J (1989) Sodium-calcium exchange current. Dependence on internal Ca++ and Na+ and competetive binding of external Na and Ca++. J Gen Physiol 93:1129–1145
Moffat MP (1989) Amiloride modifies the response of canine Purkinje fibres to conditions of ischemia und reperfusion. J Mol Cell Cardiol 21:S143 (Abstract)
Mohabir R, Lee HC, Kurz RW, Clusin WT (1991) Effects of ischemia and hypercarbic acidosis on myocyte calcium transients, contraction, and pHi in perfused rabbit hearts. Circulat Res 69:1525–1537
Murphy E, Perlman M, London RE, Steenbergen C (1991) Amiloride delays the ischemia induced rise in cytosolic free calcium. Circulat Res 68:1250–1258
Neely JR, Feuvray D (1981) Metabolic products and myocardial ischemia. Am J Physiol 102:282–291
Neely JR, Morgan HE (1974) Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Ann Rev Physiol 36:413–459
Neely JR, Rovetto MJ, Whitmer JT, Morgan HE (1973) Effects of ischemia on function and metabolism of the isolated working rat heart. Am J Physiol 225:651–658
Ng LL, Davies JE, Quinn P (1993) Intracellular pH regulation in isolated myocytes from adult rat heart in HCO3-containing and HCO3-free media. Clin Sci 84:133–139
Ng ML, Levy MN, Zieske HA (1967) Effects of changes of pH and carbon dioxide tension on left ventricular performance. Am J Physiol 213:115–120
Oh JK, Shub C, Ilstrup DM, Reeder GS (1985) Creatine kinase release after successful percutaneous transluminal coronary angioplasty. Amer Heart J 109:1225–1231
Opie LH, Coetzee WA (1988) Role of calcium ions in reperfusion arrhythmias: Relevance to pharmacologic intervention. Cardiovasc Drugs Ther 2:623–636
Pannier JL, Leusen I (1968) Contraction characteristics of papillary muscle during changes in acid-base composition of the bathing-fluid. Arch Int Phys Biochem 76:624–634
Penny WJ (1984) The deleterious effects of myocardial catecholamines on cellular electrophysiology and arrhythmias during ischemia and reperfusion. Eur Heart J 5:960–973
Phillips JH (1982) Dynamic aspects of chromaffin granule structure. Neuroscience 7:1595–1609
Pierce GN, Maddaford TG, Kroeger EA, Cragoe EJ (1990) Protection by benzamil against dysfunction and damage in rat myocardium after calcium depletion and repletion. Am J Physiol 258:H17-H23
Pike MM, Kitakaze M, Marban E (1990) 23Na-NMR measurements of intracellular sodium in intact perfused ferret hearts during ischemia and reperfusion. Am J Physiol 259:H1767-H1773
Piwnica-Worms D, Jacob R, Shigeto N, Horres CR, Lieberman M (1986) Na/H exchange in cultured chick heart cells: Secondary stimulation of electrogenic transport during recovery from intracellular acidosis. J Mol Cell Cardiol 18:1109–1116
Poole-Wilson PA (1984) Therapeutic approaches to myocardial infarct size limitation. In: Hearse DJ, Yellon DM (eds) What causes cell death. Raven press, New York, pp 43–60
Poole-Wilson PA (1989) Regulation of intracellular pH in the myocardium; relevance to pathology. Molec Cell Biochem 89:151–155
Rabkin SW (1989) Comparison of the effect of amiloride and its analogue dichlorobenzamil on cardiac chronotropic responses to Ouabain in myocardial cell aggregates in culture. Pharmacology 39:230–239
Rasmussen HH, Cragoe EJ, Ten Eick RE (1989) Na+-dependent activation of Na+−K+ pump in human myocardium during recovery from acidosis. Am J Physiol 256:H256-H264
Regan TJ, Broisman L, Haider B, Eaddy C, Oldewurtel A (1980) Dissociation of myocardial sodium and potassium alterations in mild versus severe ischemia. Am J Physiol 238:H575-H580
Rouslin W (1983) Protonic inhibition of the mitochondrial oligomycin-sensitive adenosine 5′-triphosphatase in ischemic and autolyzing cardiac muscle. J Biol Chem 258:9657–9661
Rouslin W, Erickson JL (1986) Factors affecting loss of mitochondrial functioning in autolyzing cardiac muscle. J Mol Cell Cardiol 18:1187–1195
Sack S, Mohri M, Schwarz ER, Arras M, Schaper J, Schaper W (1992) Inhibition of Na+/H+ exchange prevents ventricular fibrillation and preserves function in porcine stunned myocardium. J Mol Cell Cardiol 24:S92 (Abstract)
Schadler M (1967) Proportionale Aktivierung von ATPase-Aktivität und Kontraktionsspannung durch Calciumionen in isolierten kontraktilen Strukturen verschiedener Muskelarten. Pfluegers Arch 296:70–90
Schaffer SW, Safer B, Ford C, Illingworth J, Williamson JR (1978) Respiratory acidosis and its reversibility in perfused rat heart: regulation of citric acid cycle activity. Am J Physiol 234:H40-H51
Schelberg HR, Buxton D (1988) Insights into coronary artery disease gained from metabolic imaging. Circulat Res 78:496–505
Scheufler E, Henrichs M, Guttmann I, Mozes A, Wilffert B (1993) Effect of the Na/H exchange inhibitor Ethyl-Isopropyl-Amiloride (EIPA) during ischaemia and reperfusion. Brit J Pharmacol 108:118P
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 109:562–568
Scholz W, Albus U, Linz W, Martorana P, Lang HJ, Schölkens BA (1992) Effects of Na+/H+ exchange inhibitors in cardiac ischemia. J Mol Cell Cardiol 24:731–739
Scholz W, Albus U, Linz W, Schölkens BA (1991) Effect of Na+/H+ exchange inhibition in cardiac ischemia. Eur Heart J 12 (Suppl):124 (Abstr)
Schömig A, Kurz T, Richardt G, Schömig E (1988) Neuronal sodium homoeostasis and axoplasmic amine concentration determine calcium-independent noradrenaline release in normoxic and ischemic rat heart. Circulat Res 63:214–226
Schömig A, Richardt G (1990) The role of catecholamines in ischemia. J Cardiovasc Pharmacol 16:S105-S112
Sharma GP, Varley KG, Kim SW, Barwinsky J, Cohen M, Dhalla NS (1975) Alterations in energy metabolism and ultrastructure upon reperfusion of the ischemic myocardium after coronary occlusion. Am J Cardiol 36:234–243
Shen AC, Jennings RB (1972) Myocardial calcium and magnesium in acute ischemic injury. Am J Pathol 67:417–440
Smith HW (1926) The actions of acids on turtle muscle with reference to the penetration of anions. Am J Physiol 76:411–447
Steenbergen C, Deleeuw G, Rich T, Williamson JR (1977) Effects of acidosis and ischemia on contractility and intracellular pH of rat heart. Circulat Res 41:849–858
Steenbergen C, Murphy E, Levy L, London RE (1987) Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circulat Res 60:700–707
Steenbergen C, Murphy E, Watts JA, London RE (1990) Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circulat Res 66:135–146
Steenbergen C, Perlman ME, London RE, Murphy E (1993) Mechanisms of preconditioning: ionic alterations. Circulat Res 72:112–125
Stute N, Trendelenburg U (1984) The outward transport of axoplasmic noradrenaline induced by a rise of the sodium concentration in the adrenergic nerve endings of the rat vas deferens. Naunyn Schmiedebergs Arch Pharmacol 327:124–132
Tani M, Neely JR (1989) Role of intracellular Na+ in Ca++ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Circulat Res 65:1045–1056
Tani M, Neely JR (1990) Na+ accumulation increases Ca++ overload and impairs function in anoxis rat heart. J Mol Cell Cardiol 22:57–72
Tonnessen TI, Sandvig K, Olsnes S (1990) Role of Na+−H+ and Cl−−HCO3-antiports in the regulation of cytosolic pH near neutrality. Am J Physiol 258:C1117-C1126
Vandenberg JI, Metcalfe JC, Grace AA (1993) Mechanisms of pHi recovery after global ischemia in the perfused heart. Circulat Res 72:993–1003
Vaughan-Jones RD, Wu ML (1990) Extracellular H+ inactivation of Na+−H+ exchange in the sheep cardiac Purkinje fibre. J Physiol 428:441–466
Wallert MA, Fröhlich O (1989) Na+−H+ exchange in isolated myocytes from adult rat heart. Am J Physiol 26:C207-C213
Wang HH, Katz RL (1965) Effects of changes in coronary blood pH on the heart. Circulat Res 17:114–122
Weiss ES, Hoffmann EJ, Phelps ME, Welch MJ, Henry PD, Ter-Porgossian MM, Sobel BE (1976) External detection and visualization of myocardial ischemia with11C-substrates in vitro and in vivo. Circulat Res 39:24–32
Weiss RG, Lakatta EG, Gerstenblith G (1990) Effects of amiloride on metabolism and contractility during reoxygenation in perfused rat heart. Circulat Res 66:1012–1022
Weissberg PL, Little PJ, Cragoe EJ, Bobik A (1989) The pH of spontaneously beating cultured rat heart cells is regulated by an ATP-calmodulin-dependent Na+/H+ antiport. Circulat Res 64:676–685
Williamson JR, Schaffer SW, Ford C, Safer B (1976) Contribution of tissue acidosis to ischemic injury in the perfused rat heart. Circulation 53:I3-I14
Winkler H, Apps DK, Fischer-Colbrie R (1986) The molecular function of adrenal chromaffin granules: established facts and unresolved topics. Neuroscience 18:261–290
Wollenberger A, Krause EG (1968) Metabolic control characteristics of the acutely ischemic myocardium. Am J Cardiol 22:349–359
Wright J, Maridonneau-Parini I, Cragoe EJ, Schwartz JH, Tauber AI (1988) The role of the Na+/H+ antiporter in human neutrophil NADPH-oxidase activation. J Leukocyte Biol 43:183–186
Zhao-Ping L, Chao-Shu T, Jing-Yi S (1991) Role of Na+−Ca++ exchange system in the pathogenesis of myocardial Ischemia-Reperfusion damage. Science in China 34:599–605
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Scholz, W., Albus, U. Na+/H+ exchange and its inhibition in cardiac ischemia and reperfusion. Basic Res Cardiol 88, 443–455 (1993). https://doi.org/10.1007/BF00795411
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00795411