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Contractile failure in early myocardial ischemia: Models and mechanisms


In early myocardial ischemia we find a number of salient electrical and ionic alterations. This article reviews action potential shortening, K accumulation, and contractile failure. Enhanced K efflux during early myocardial ischemia has been attributed to a number of mechanisms, including: the inhibition of active K uptake, osmotic changes, efflux of K ions linked to anion extrusion, cation exchange, altered cellular energy levels, in particular, the opening of ATP-dependent K channels, the involvement of other ion channels, a H/K-ion exchanger, and a catecholamine-dependent pathway. The different mechanisms are discussed. Action potential shortening was described as a salient characteristic of myocardial ischemia in 1954 by Trautwein and Dudel, and was attributed to enhanced outward current. Recently it has been shown by several authors that ATP-dependent potassium channels play a key role in this context. Contractile failure in early myocardial ischemia has been explained by shortening of the action potential duration, reduced cytoplasmic free calcium levels, intracellular acidification, and a rise in inorganic phosphate and Mg. In summary, it is concluded that ATP-dependent K channels may be involved in each of these three phenomena.

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  1. 1.

    Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischaemia and infarction.Physiol Rev 1989;69:1049–1169.

  2. 2.

    Kleber A. Extracellular potassium accumulation in acute myocardial ischaemia.J Mol Cell Cardiol 1984;16:389–394.

  3. 3.

    McDonald TF, Hunter EG, MacLeod DP. Adenosinetriphosphate partition in cardiac muscle with respect to transmembrane electrical activity.Pflugers Arch 1971;325:305–322.

  4. 4.

    Isenberg G, Vereeke J, van der Heyden G, Carmeliet E. The shortening of the action potential by DNP in guinea-pig ventricular myocytes is mediated by an increase of time-independent K+-conductance.Pflügers Arch 1983;397:251–259.

  5. 5.

    Procacci P, Zoppie M. Heart pain. In: Wall PD, Melzack R, eds.Textbook of Pain. Edinburgh: Churchill Livingstone, 1984;308–318.

  6. 6.

    Lowry OH, Krayer A, Hastings AB, Tucker RP. Effect of anoxemia on myocardium of isolated heart of the dog. ProcSoc Exp Biol Med 1942;49:670–674.

  7. 7.

    Harris AS, Bisteni A, Russell RA, Brigham JC, Firestone JE. Excitatory factors in ventricular tachycardia resulting from myocardial ischaemia: Potassium a major excitant.Science 1954;199:200–203.

  8. 8.

    Chiarac P.De motu cardis, adversaria analytica, Monspellii, 1698.

  9. 9.

    Kloner RA, Braunwald E. Observations on experimental myocardial ischaemia.Cardiovasc Res 1980;14:371–395.

  10. 10.

    Allen DG, Orchard CH. Myocardial contractile function during ischaemia and hypoxia.Circ Res 1987;60:153–167.

  11. 11.

    Kimura S, Basset AL, Furukawa T, Cuevas J, Myerburg RJ. Electrophysiological properties and responses to simulated ischaemia in cat ventricular myocytes of endocardial and epicardial origin.Circ Res 1990;66:469–477.

  12. 12.

    De Hemptinne A, Marrannes R, Vanheel, B. Double-barrelled intracellular pH-electrode: Construction and illustration of some results. In: Nuccitelli R, Deamer DW, eds.Intracellular pH: Its Measurement, Regulation and Utilization in Intracellular Function. New York: Alan R. Liss, 1982:7–19.

  13. 13.

    Gasser R, Vaughan-Jones RD. Mechanism of potassium efflux and action potential shortening during ischaemia in isolated cardiac muscle.Physiology 1990;431:713–741.

  14. 14.

    Scheuer J, Stezoski SW. Effects on high-energy phosphate depletion and repletion on the dynamics and electrocardiogram of isolated rat hearts.Circ Res 1968;23:519–530.

  15. 15.

    Weiss J, Shine I. Extracellular K+-accumulation during myocardial ischaemia in isolated rabbit heart.Am J Physiol 1982;242:H619-H628.

  16. 16.

    Hill JL, Gettes LS. Effect of acute coronary artery occlusion on local myocardial extracellular K+-activities in swine.Circulation 1980;61:768–778.

  17. 17.

    Weiss J, Shine I. Extracellular K+-accumulation during early myocardial ischaemia, implications for arrythmogenesis.J Mol Cell Cardiol 1981;13:699–704.

  18. 18.

    Kleber A. Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischaemia in isolated perfused guinea-pig hearts.Circ Res 1983;52:442–450.

  19. 19.

    Wilde AAM, Peters RJG, Janse MJ. Catecholamine release and potassium accumulation in the isolated globally ischaemic rabbit heart.J Mol Cell Cardiol 1988;20:887–896.

  20. 20.

    Lopez JF, Orchard RC. Effects of verapamil on the extracellular K+ rise during myocardial ischaemia in dogs.Cardiovasc Res 1985;19:363–369.

  21. 21.

    Mori H, Sakurai K, Miyazaki T, Ogawa S, Nakamura Y. Local myocardial electrogram and potassium concentration changes in superficial and deep intramyocardium and their relations with early ischaemic ventricular arrhythmias.Cardiovasc Res 1987;21:447–454.

  22. 22.

    Poole-Wilson PA. Potassium and heart. In: Morgan DB, ed.Clinics in Endocrinology and Metabolism Electrolyte Disorders. London: W.B. Saunders, 1984:249–268.

  23. 23.

    Conrad GL, Rau EE, Shine KI. Creatine kinase release, potassium-42 content, and mechanical performance in anoxic rabbit myocardium.J Clin Invest 1979;64:155–161.

  24. 24.

    Rau EE, Shine KI, Langer GA. Potassium exchange and mechanical peformance in anoxic mammalian myocardium.Am J Physiol 1977;232:H85-H97.

  25. 25.

    Calkins E, Taylor IM, Hastings B. Potassium exchange in the isolated rat diaphragm: Effect of anoxia and cold.Am J Physiol 1954;177:211–218.

  26. 26.

    Goerke J, Page E. Cat heart muscle in vitro: VII. Potassium exchange in papillary muscles.J Gen Physiol 1965;48:933–948.

  27. 27.

    Shine K. Ionic events in ischaemia and anoxia.Am J Pathol 1981;102:256–261.

  28. 28.

    Tranum-Jensen J, Janse MJ, Fiolet JWT, Krieger WJG, Naumann d'Alnoncourt C, Durrer D. Tissue osmolality, cell swelling, and reperfusion in acute regional myocardial ischaemia in the isolated porcine heart.Circ Res 1981;49:364–381.

  29. 29.

    Gaspardone A, Shine KI, Seabrooke SR, Poole-Wilson PA. Potassium loss from rabbit myocardium during hypoxia: Evidence for passive efflux linked to anion extrusion.J Mol Cell Cardiol 1986;18:389–399.

  30. 30.

    Crake T, Kirby MS, Poole-Wilson PA. Potassium efflux from the myocardium during hypoxia: Role of lactate ions.Cardiovasc Res 1987;21:886–891.

  31. 31.

    Boyle PJ, Conway EJ. Potassium accumulation in muscle and associated changes.J Physiol 1941;100:1–63.

  32. 32.

    Mainwood GW, Lucier GE. Fatigue and recovery on isolated frog skeletal muscles: The effects of bicarbonate concentration and associated potassium loss.Can Physiol Pharmacol 1972;50:132–142.

  33. 33.

    Castle NA, Haylett DG. Effect of channel blockers on potassium efflux from metabolically exhausted frog skeletal muscle.J Physiol 1987;383:31–43.

  34. 34.

    Case RB. Ion alterations during myocardial ischaemia.Cardiology 1971/72;56:245–262.

  35. 35.

    Garlick PB, Radda GK, Seeley PJ. Studies of acidosis in the ischaemic heart by phosphorus nuclear magnetic resonance.Biochem J 1979;184:547–554.

  36. 36.

    Vaughan-Jones RD. Non-passive chloride distribution in mammalian heart muscle: Microelectrode measurements of the intracellular chloride activity.Physiology 1979;295:83–109.

  37. 37.

    Schwarz H, Wood JM, Allen JC, et al. Biochemical and morphologic correlates of cardiac ischaemia. I. Membrane systems.Am Cardiol 1973;32:46–61.

  38. 38.

    Lai F, Scheuer J. Early changes in myocardial hypoxia: Relations between mechanical function, pH and intracellular compartmental metabolites.Mol Cell Cardiol 1975;7:289–303.

  39. 39.

    Coburn RF, Grubb W, Aronson R. Effect of cyanide on oxygen sensitive tension in rabbit aorta.Fed Proc 1976;35:698.

  40. 40.

    Vleugels A, Vereke AJ, Carmeliet E. Ionic currents during hypoxia in voltage-clamped cat ventricular muscle.Circ Res 1980;47:501–508.

  41. 41.

    Trautwein W, Gottstein V, Dudel J. Der Aktionsstrom der Myokardfaser im Sauerstopffmangel.P \(\ddot f\) lugers 1954;260:40–60.

  42. 42.

    Trautwein W, Dudel J. Aktionspotential und Kontraktion des Herzmuskels im Sauerstoffmangel.Pflügers Arch 1956;263:23–32.

  43. 43.

    Attwell D, Eisner D, Cohen I. Voltage clamp and tracer flux data: Effects of a restricted extracellular space.Q Rev Biophys 1979;12:213–261.

  44. 44.

    DiFrancesco D, Noble D. A model of cardiac electrical activity incorporating ionic pumps and concentration changes.Physiol Trans R Soc Lond 1985;B307:353–398.

  45. 45.

    Isenberg G. Cardiac Purkinje fibres: Ca2+ controls steady state potassium conductance.Pfügers Arch 1977;371:71–76.

  46. 46.

    Noma A. ATP-regulated K+-channels in cardiac muscle.Nature 1983;305:147–148.

  47. 47.

    Aschroft FM. Adenosine-5′-triphosphate-sensitive potassium channels.Ann Rev Neurosci 1988;11:97–118.

  48. 48.

    Noma A, Shibasaki T. Membrane current through adenosine-triphosphate-regulated potassium channels in guineapig ventricular cells.J Physiol 1985;363:463–480.

  49. 49.

    Gasser R, Vaughan-Jones RD. Myocardial ischaemia: Release of potassium can be inhibited by tolbutamide glibenclamide in isolated guinea-pig papillary muscle.J Physiol 1989;418:43P.

  50. 50.

    Kantor PF, Coetzee WA, Carmeliet EE, Dennis SC, Opie LH. Reduction of ischaemic K+-loss and arrhythmias in rat hearts. Effect of glibenclamide, a sulphonylurea.Circ Res 1990;66:478–485.

  51. 51.

    Daut J, Maier-Rudolph W, von Beckenrath N, Mehrke G, Gunther K, Goedel-Meinen L. Hypoxic dilation of coronary arteries is mediated by ATP-sensitive potassium channels.Science 1990;247:1341–1344.

  52. 52.

    Davies NW. Modulation of ATP-sensitive K+-channels in skeletal muscle by intracellular protons.Nature 1990;343:375–377.

  53. 53.

    Vanheel B, De Hemptinne A. Effects of acidosis on extracellular K+-accumulation and surface pH in isolated ischaemic guinea-pig papillary muscle. Precirculated abstract, Glasgow Meeting of the Physiological Society, June 1990, abstract book, 1990, 11.

  54. 54.

    Kim D, Clapham DE. Potassium channels in cardiac cells activated by arachidonic acid and phospholipids.Science 1989;244:1174–1176.

  55. 55.

    Van der Vusse GJ, Roementh HM, Prinzen FW, Coumans WA, Reneman RS. Uptake and tissue content of fatty acids in dog myocardium under normoxic and ischaemic conditions.Circ Res 1982;50:538.

  56. 56.

    Poole-Wilson PA, Cameron IR. Intracellular pH and K of cardiac and skeletal muscle in acidosis and alkalosis.Am J Physiol 1975;229:1305–1310.

  57. 57.

    Poole-Wilson PA, Langer GA. Effect of pH on ionic exchange and function in rat and rabbit myocardium.Am J Physiol 1975;229:570–581.

  58. 58.

    Gerlings ED, Miller DT, Gilmore JP. Oxygen availability: A determinant of myocardial potassium balance.Am J Physiol 1969;216:559–562.

  59. 59.

    De Mello WC. Metabolism and electrical activity of the heart: Action of 2–4 dinitrophenol and ATP.Am J Physiol 1959;196:377–380.

  60. 60.

    Vleugels A.Hypoxia and the Duration of the Cardiac Action Potential. Leuven: Acco, 1979.

  61. 61.

    Carmeliet E. Cardiac transmembrane potentials and metabolism.Circulation 1978;42:577–587.

  62. 62.

    Webb JL, Hollander PB. Metabolic aspects of the relationship between the contractility and membrane potentials of the rat atrium.Circ Res 1956;9:618–628.

  63. 63.

    McDonald FF, MacLeod DP. Metabolism and the electrical activity of anoxic ventricular muscle.J Physiol 1973;229:559–582.

  64. 64.

    Schneider JA, Sperelakis N. The demonstration of energy dependence of the isoproterenol-induced transcellular Ca2+ current in isolated perfused guinea pig hearts. An explanation for mechanical failure of ischaemic myocardium.J Surg Res 1987;16:389–403.

  65. 65.

    Kohlhardt M, Kuebler M. The influence of metabolic inhibitors upon the transmembrane slow inward current in the mammalian ventricular myocardium.Naunyn Schmiedebergs Arch Pharmacol 1975;290:265–274.

  66. 66.

    Nargeot J, Challice CE, Tau KS, Garnier D. Influence of metabolic inhibition by NaCN on electrical and mechanical activities of frog atrial fibres: Studies using current and voltage clamp.J Mol Cell Cardiol 1978;10:469–485.

  67. 67.

    Bassingthwaighte JB, Fry CH, McGuigan JAS. Relationship between internal calcium and outward current in mammalian ventricular muscle, a mechanism for the control of the action potential duration?J Physiol 1976;262:15–37.

  68. 68.

    McDonald FF, MacLeod DP. Anoxia-recovery cycle in ventricular muscle: Action potential duration, contractility and ATP content.Pflügers Arch 1971;325:305–322.

  69. 69.

    Fosset M, De Weille JR, Green RD, Schmid-Antomarchi H, Lazdunski M. Antidiabetic sulphonylureas control action potential properties in heart cells via high affinity receptors that are linked to ATP-dependent K+-channels.J Biol Chem 1988;263:7933–7936.

  70. 70.

    Lederer WJ, Nichols CG, Smith: The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition.J Physiol 1989;413:329–349.

  71. 71.

    Taniguchi J, Noma A, Irisawa H. Modification of the cardiac action potential by intracellular injection of adenosine triphosphate and related substances in guinea pig single ventricular cells.Circ Res 1983;53:131–139.

  72. 72.

    Noble D. A modification of the Hodgkin-Huxley equations applicable to Purkinje fibre action and pacemaker potentials.J Physiol 1962;160:317–352.

  73. 73.

    Kavaler F, Hyman PM, Lefkowitz RB. Positive and negative inotropic effects of elevated extracellular potassium in mammalian ventricular muscle.J Gen Physiol 1972;60:351–365.

  74. 74.

    Erichsen E. On the influence of the coronary circulation on the action of the heart.Lond Med Gazette 1842;II:561–564.

  75. 75.

    Allen DG, Harris MB, Smith GL. Failure of action potentials during cyanide exposure in glycogen-depleted ferret ventricular muscle.J Physiol 1987;387:65P.

  76. 76.

    McDonald FF, Hayashi H, Ponnambolam C, Watanabe T. Electrical activity and tension in guinea pig ventricular muscle during and after metabolic depression. In: Yarnada K, Katz AM, Toyama J, eds.Cardiac Function Under Ischaemia and Hypoxia. Nagoya, Japan: University of Nagoya Press, 1986.

  77. 77.

    Morad M, Goldman Y. Excitation-contraction coupling in heart muscle: Membrane control of development of tension.Prog Biophys Mol Biol 1973;27:257–313.

  78. 78.

    Stern MD, Chien AM, Capogrossi MC, Pelto DJ, Lakatta EG. Direct observation of the “oxygen-paradox” in single rat ventricular myocytes.Circ Res 1985;56:899–903.

  79. 79.

    Allen DG, Morris PG, Orchard CH, Pirolo JS. A nuclear magnetic resonance study of metabolism in the ferret heart during hypoxia and inhibition of glycolysis.J Physiol 1985;361:185–204.

  80. 80.

    Smith JS, Caronardo R, Meissner G. Sarcoplasmic reticulum contains adenine nucleotide-activated calcium channels.Nature 1985;316:446–449.

  81. 81.

    Vanheel B, Leybaert L, De Hemptinne A, Leusen I. Simulated ischaemia and intracellular pH in isolated ventricular muscle.Am J Physiol 1989;257:C365-C376.

  82. 82.

    Baily IA, Williams SR, Radda GK, Godian DG. Activity of phosphorylase in total global ischaemia in the rat heart.Biochem J 1981;196:171–178.

  83. 83.

    Gaskell WH. On the tonicity of the heart and blood vessels.J Physiol 1880;3:48–75.

  84. 84.

    Bountra C, Vaughan-Jones RD. Effect of intracellular and extracellular pH on contraction in isolated mammalian cardiac muscle.J Physiol 1989;418:163–187.

  85. 85.

    Katz AM, Hecht HH. The early “pump” failure of the ischaemic heart.Am J Med 1969;47:497–502.

  86. 86.

    Jacobus WE, Poses IH, Lucas SK, Kallman CH, Weisfeldt ML, Floherty JT. The role of intracellular pH in the control of normal and ischaemic myocardial contractility: A P nuclear magnetic resonance and mass spectrometry study. In: Nuccitelli R, Deamer DW, eds.Intracellular pH: Its Measurement, Regulation and Utilization in Cellular Function, New York: Alan R. Liss, 1982;537–565.

  87. 87.

    Williamson JR. Glycolytic control mechanism. II. Kinetics of intermediate changes during the aerobic-anoxic transition in perfused rat heart.J Biol Chem 1966;241:5026–5036.

  88. 88.

    Matthews PM, Radda GK, Taylor DJ. A “p.n.m.r.” study of metabolism in the hypoxic perfused heart.Biochem Soc Trans 1981;9:236–237.

  89. 89.

    Herzig JW, Ruegg JC. Myocardial cross-bridge activity and its regulation by Ca2+, phosphate and strech. In: Riecker G, Weber A, Goodwin J, eds.Myocardial Failure International Boehring Mannheim Symposium, 1977:134–152.

  90. 90.

    Kentish JC. The effects of organic phosphate on force production in skinned muscles from rat ventricle.J Physiol 1986;370:585–604.

  91. 91.

    Fabiato A, Fabiato F. Effects of magnesium on contractile activation of skinned cardiac cells.J Physiol 1975;249:497–517.

  92. 92.

    Hess P, Metzger P, Weingard R. Free magnesium in sheep, ferret and frog striated muscle at rest measured with ion-selective microelectrodes.J Physiol 1982;333:173–188.

  93. 93.

    Buri A, McGuigan JAS. The regulation of the intracellular free magnesium concentration in isolated ferret ventricular papillary muscle.J Physiol 1990;423:110P.

  94. 94.

    Wolfe CL, Gilbert HF, Brindle KM, Radda GK. Determination of buffering capacity of rat myocardium during ischaemia.Biochim Biophys Acta 1988;971:9–20.

  95. 95.

    Berne RM, Rubio R. Coronary circulation. In: Berne RM, Sperelakis N, Geiger SR, eds.The Cardiovascular System, Handbook of Physiology, Vol. I, The Heart. Bethesda, MD, American Physiological Society, 1979:837–952.

  96. 96.

    Gasser R, Dienstl F. Acute myocardial infarction: An episodic event of several coronary spasms followed by dilatation?Clin Physiol 1986;6:397–403.

  97. 97.

    Hacket D, Davies G, Chierchia S, Maseri A. Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy.N Engl J Med 1987;317:1055–1059.

  98. 98.

    Levey GS, Lasseter KC, Palmer RF. Sulphonylureas and the heart.Ann Rev Med 1974;69–74.

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Correspondence to Univ.-Doz. Robert N. A. Gasser M.D., D. Phil.

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Gasser, R.N.A., Klein, W. Contractile failure in early myocardial ischemia: Models and mechanisms. Cardiovasc Drug Ther 8, 813–822 (1994).

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Key words

  • potassium
  • myocardium
  • ischemia
  • KATP channel
  • contractile failure