Calcium Ions and Ventricular Arrhythmias

  • L. H. Opie
  • W. A. Coetzee
  • W. T. Clusin


Considerable experimental evidence suggests that calcium antagonist agents can have antiarrhythmic effects on both ischaemic and reperfusion arrhythmias. Furthermore, adequate electrophysiological mechanisms have been described whereby an increased cytosolic calcium could promote ischaemic or reperfusion arrhythmias, acting by somewhat different mechanisms. None the less, calcium antagonists are not recognized as ventricular antiarrhythmic agents and this paradox will briefly be analysed in this chapter after a review of the basic experimental evidence.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Allen, D. G., Lee, J. A. and Smith, G. L. (1989). The consequences of simulated ischaemia on intracellular calcium and tension in isolated ferret ventricular muscle. J. Physiol. 410, 297–323PubMedPubMedCentralCrossRefGoogle Scholar
  2. Allshire, A., Piper, M., Cuthbertson, K. S. R. and Cobbold, P. H. (1987). Cytosolic free Ca2+ in single rat heart cells during anoxia and reoxygenation. Biochem. J., 244, 381–385PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alto, L. E. and Dhalla, N. S. (1981). Role of changes in microsomal calcium uptake in the effects of reperfusion of CaZ+-deprived rat hearts. Circ. Res., 48, 17–24PubMedCrossRefGoogle Scholar
  4. Berlin, J. R., Cannel, M. B., Goldman, W. F., et al. (1986). Subcellular calcium in-homogeneity indicated by fura-2 develops with calcium overload in single rat heart cells. J. Physiol., 371, 200PGoogle Scholar
  5. Bhattacharyya, M. L. and Vassalle, M. (1981). The effect of metabolic inhibitors on strophanthidin-induced arrhythmias and contracture in cardiac Purkinje fibers. J. Pharmacol. Exp. Ther., 219, 75–84PubMedGoogle Scholar
  6. Blake, K., Clusin, W. T., Franz, M. R. and Smith, N. A. (1988). Mechanism of depolarization in the ischaemic dog heart: Discrepancy between T-Q potentials and potassium accumulation. J. Physiol., 397, 307–330PubMedPubMedCentralCrossRefGoogle Scholar
  7. Blake, K., Smith, N. A. and Clusin, W. T. (1986). Rate dependence of ischaemic myocardial depolarization-evidence for a novel membrane current. Cardiovasc. Res., 20, 557–562PubMedCrossRefGoogle Scholar
  8. Callewaert, G., Vereecke, J. and Carmeliet, E. (1986). Existence of a calcium-dependent potassium channel in the membrane of cow cardiac Purkinje cells. Pflugers Arch., 406, 424–426PubMedCrossRefGoogle Scholar
  9. Cannell, M. B. and Lederer, W. J. (1986). The arrhythmogenic current Iti in the absence of electrogenic sodium-calcium exchange in sheep cardiac Purkinje fibers. J. Physiol., 374, 201–219PubMedPubMedCentralCrossRefGoogle Scholar
  10. Capogrossi, M. C., Houser, S. R., Bahinski, A., et al. (1987). Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential. Circ. Res., 61, 498–503PubMedCrossRefGoogle Scholar
  11. Clusin, W. T. (1983). Caffeine induces a transient inward current in cultured cardiac cells. Nature, 301, 248–250PubMedCrossRefGoogle Scholar
  12. Clusin, W. T. (1987). What is the solution to sudden cardiac death: Calcium modulation or arrhythmia clinics? Cardiovasc. Drugs Ther., 1, 335–342PubMedCrossRefGoogle Scholar
  13. Clusin, W. T. (1989). Role of calcium-activated ion currents in the heart. In Sperelakis, N. (Ed.), Physiology and Pathophysiology of the Heart, 2nd edn. Kluwer Academic Publishers, Boston, pp. 95–114CrossRefGoogle Scholar
  14. Clusin, W. T., Buchbinder, M. and Harrison, D. C. (1983). Calcium overload, ‘injury’ current, and early ischaemic cardiac arrhythmias-a direct connection. Lancet, 1, 272–274PubMedCrossRefGoogle Scholar
  15. Coetzee, W. A., Biermans, G., Callewaert, G., et al. (1988). The effect of inhibition of mitochondrial energy metabolism on the transient inward current of isolated guinea-pig ventricular myocytes. J. Mot. Cell. Cardiol., 20, 181–185CrossRefGoogle Scholar
  16. Coetzee, W. A., Dennis, S. C., Opie, L. H. and Muller, C. A. (1987a). Calcium channel blockers and early ischemic ventricular arrhythmias: electrophysiological versus antiischemic effects. J. Mot. Cell. Cardiol., 19 (Suppl. II), 77–97CrossRefGoogle Scholar
  17. Coetzee, W. A. and Opie, L. H. (1987). Effects of components of ischemia and metabolic inhibition on delayed afterdepolarizations in guinea-pig papillary muscle. Circ. Res., 61, 157–167PubMedCrossRefGoogle Scholar
  18. Coetzee, W. A., Opie, L. H. and Saman, S. (1987b). Proposed role of energy supply in the genesis of delayed afterdepolarizations-implications for ischemic or reperfusion arrhythmias. J. Mot. Cell. Cardiol., 19 (Suppl. V), 13–21CrossRefGoogle Scholar
  19. Coetzee, W. A., Scamps, F., Carmeliet, E. E., et al. (1987c). Modulation of the transient inward current by metabolic inhibition and intracellular ATP: Implications for ischemic arrhythmias [Abstract]. Circulation, 76 (Suppl. IV), IV-16Google Scholar
  20. Colquhoun, D., Neher, E., Reuter, H. and Stevens, C. F. (1981). Inward current channels activated by intracellular Ca" in cultured cardiac cells. Nature, 294, 752–754PubMedCrossRefGoogle Scholar
  21. Coraboeuf, E. and Carmeliet, E. (1982). Existence of two transient outward currents in sheep cardiac Purkinje fibers. Pfiugers Arch., 392, 352–359CrossRefGoogle Scholar
  22. Danish Study Group on Verapamil in Myocardial Infarction (1990). Effects of verapamil on mortality and major events after acute myocardial infarction [The Danish Verapamil Infarction Trial II-DAVIT II]. Am. J. Cardiol., 66, 779–785CrossRefGoogle Scholar
  23. Dean, J. W. and Lab, M. J. (1989). Arrhythmia in heart failure: role of mechanically induced changes in electrophysiology. Lancet, 1, 1309–1311PubMedCrossRefGoogle Scholar
  24. Dennis, S. C., Coetzee, W. A., Cragoe, E. J. and Opie, L. H. (1990). Effects of proton buffering and of amiloride derivatives on reperfusion arrhythmias in isolated rat hearts: possible evidence for an arrhythmogenic role of Na+-H+ exchange. Circ. Res., 66, 1156–1159PubMedCrossRefGoogle Scholar
  25. Dilly, S. G. and Lab, M. J. (1988). Electrophysiological alternans and restitution during acute regional ischemia in myocardium of the anaesthetized pig. J. Physiol., 402, 315–333PubMedPubMedCentralCrossRefGoogle Scholar
  26. Ehara, T., Noma, A. and Ono, K. (1988). Calcium-activated non-selective cation channel in ventricular cells isolated from adult guinea-pig hearts. J. Physiol., 403, 117–133PubMedPubMedCentralCrossRefGoogle Scholar
  27. Eisner, D. A. and Valdeolmillos, M. (1986). A study of intracellular calcium oscillations in sheep cardiac Purkinje fibers measured at the single cell level. J. Physiol., 372, 539–556PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fedida, D., Noble, Y., Shimoni, Y. and Spindler, A. J. (1987). Inward current related to contraction in guinea-pig ventricular myocytes. J. Physiol., 385, 565–589PubMedPubMedCentralCrossRefGoogle Scholar
  29. Feher, J. J., LeBolt, W. R. and Marson, N. H. (1989). Differential effects of global ischemia on the ryanodine-sensitive and ryanodine-insensitive Cat2+ uptake of the cardiac sarcoplasmic reticulum. Circ. Res., 65, 1400–1408PubMedCrossRefGoogle Scholar
  30. Ferrari, R., Ceconi, C., Curello, S., et al. (1988). Metabolic changes during post-ischaemic reperfusion. J. Mot. Cell. Cardiol., 20 (Suppl. II), 119–133CrossRefGoogle Scholar
  31. Ferrier, G. R., Moffat, M. P. and Lukas, A. (1985). Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Studies on isolated canine ventricular tissues. Circ. Res., 56, 184–194PubMedCrossRefGoogle Scholar
  32. Franz, M. R., Burkhoff, D., Spurgeon, H., et al. (1986). In vitro validation of a new catheter technique for recording monophasic action potentials. Eur. Heart J., 7, 34–41PubMedGoogle Scholar
  33. Giles, W. and Imaizuma, Y. (1988). Comparison of potassium currents in rabbit atrial and ventricular cells. J. Physiol., 405, 123–145PubMedPubMedCentralCrossRefGoogle Scholar
  34. Hearse, D. J. (1977). Reperfusion of the ischaemic myocardium. J. Mot. Cell. Cardiol., 9, 605–616CrossRefGoogle Scholar
  35. Hill, J. A., Coronado, R. and Strauss, H. C. (1988). Reconstitution and characterization of a calcium-activated channel from heart. Circ. Res., 62, 411–415PubMedCrossRefGoogle Scholar
  36. Horackova, M. (1986). Excitation-contraction coupling in isolated adult ventricular myocytes from the rat, dog, and rabbit: Effects of various inotropic interventions in the presence of ryanodine. Can. J. Physiol. Pharmacol., 64, 1473–1483PubMedCrossRefGoogle Scholar
  37. Isenberg, G. (1975). Is potassium conductance of cardiac Purkinje fibres controlled by [Ca++]? Nature, 253, 273–274CrossRefGoogle Scholar
  38. Janse, M. J., Kleber, A. G., Capucci, A., et al. (1986). Electrophysiological basis for arrhythmias caused by acute ischemia. Role of the subendocardium. J. Mot. Cell. Cardiol., 18,339–355CrossRefGoogle Scholar
  39. Kass, R. S., Lederer, W. J., Tsien, R. W. and Weingard, R. (1978a). Role of calcium ions in transient inward currents and aftercontractions induced by strophanthidin in cardiac Purkinje fibers. J. Physiol., 281, 187–208PubMedPubMedCentralCrossRefGoogle Scholar
  40. Kass, R. S., Siegelbaum, S. and Tsien, R. W. (1976). Incomplete inactivation of the slow inward current in cardiac Purkinje fibers. J. Physiol., 263, 127P-128PPubMedGoogle Scholar
  41. Kass, R. S. and Tsien, R. W. (1976). Control of action potential duration by calcium ions in cardiac Purkinje fibers. J. Gen. Physiol., 67, 599–617PubMedCrossRefGoogle Scholar
  42. Kass, R. S., Tsien, R. W. and Weingard, R. (1978b). Ionic basis of transient inward current induced by strophanthidin in cardiac Purkinje fibers. J. Physiol., 281, 209–226PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kihara, Y., Grossman, W. and Morgan, J. P. (1989). Direct measurement of changes in intracellular calcium transients during hypoxia, ischemia, and reperfusion of the intact mammalian heart. Circ. Res., 65, 1029–1044PubMedCrossRefGoogle Scholar
  44. Kimura, S., Cameron, J. S., Kozlovskis, P. L., et al. (1985). Delayed afterdepolarizations and triggered activity induced in feline Purkinje fibres by alpha-adrenergic stimulation in the presence of elevated calcium levels. Circulation, 70, 1074–1082CrossRefGoogle Scholar
  45. Kleber, A. G. (1983). Resting membrane potential, extracellular potassium activity and intracellular sodium activity during acute global ischemia in isolated perfused guinea-pig hearts. Circ. Res., 52, 442–450PubMedCrossRefGoogle Scholar
  46. Kleber, A. G., Janse, M. J., van Capelle, F. J. L. and Durrer, D. (1978). Mechanism and time course of S-T and T-Q segment changes during acute regional myocardial ischemia in the pig heart determined by intracellular and extracellular recordings. Circ. Res., 42, 603–613PubMedCrossRefGoogle Scholar
  47. Kusuoka, H., Koretsune, Y., Chacko, V. P., Weisfeldt, M. L. and Marban, E. (1990).Excitation-contraction coupling in postischemic myocardium. Does failure of activator Ca2+ transients underlie stunning? Circ. Res., 66, 1268–1276PubMedCrossRefGoogle Scholar
  48. Lab, M. J. and Lee, J. A. (1990). Changes in intracellular calcium during mechanical alternans in isolated ferret ventricular muscle. Circ. Res., 66, 585–595PubMedCrossRefGoogle Scholar
  49. Lazdunski, M., Frelin, C. and 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. Mot. Cell. Cardiol., 17, 1029–1042CrossRefGoogle Scholar
  50. Lee, H.-C., Mohabir, R., Smith, N., et al. (1988). Effect of ischemia on calcium-dependent fluorescence transients in rabbit hearts containing Indo 1. Correlation and monophasic action potentials and contraction. Circulation, 78, 1047–1059PubMedCrossRefGoogle Scholar
  51. Marban, E., Kitakaze, M., Koretsune, Y., et al. (1990). Quantification of [Ca2+]; in perfused hearts. Critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion. Circ. Res., 66, 1255–1267PubMedCrossRefGoogle Scholar
  52. Meech, R. W. (1972). Intracellular conductance in Aplysia nerve cells. Comp. Biochem. Physiol., 42A, 493–499CrossRefGoogle Scholar
  53. Multicenter Diltiazem Postinfarction Trial Research Group (1988). The effect of diltiazem on mortality and reinfarction after myocardial infarction. New Engl. J. Med., 319, 385–392CrossRefGoogle Scholar
  54. Nayler, W. G. (Ed.) (1988). Calcium Antagonists. Academic Press, New YorkGoogle Scholar
  55. Nayler, W. G., McInnes, I., Swann, J. B., et al. (1968). Some effects of iproveratril (isoptin) on the cardiovascular system. J. Pharmacol. Exp. Ther., 161, 247–261PubMedGoogle Scholar
  56. Opie, L. H. (1989). Reperfusion injury and its pharmacologic modification. Circulation, 80, 1049–1062PubMedCrossRefGoogle Scholar
  57. Opie, L. H. and Coetzee, W. A. (1988). Role of calcium ions in reperfusion arrhythmias. Relevance to pharmacological intervention. Cardiovasc. Drugs Ther., 2, 609–622CrossRefGoogle Scholar
  58. Opie, L. H. and Coetzee, W. A. (1990). Metabolic components of ischemia and fibrillation. In Zipes, D. P. and Jalife, J. (Eds), Cardiac Electrophysiology. From Cell to Bedside. Saunders, New York, pp. 456–462Google Scholar
  59. Opie, L. H., Coetzee, W. A., Dennis, S. C. and Thandroyen, F. T. (1988). A potential role of calcium ions in early ischemic and reperfusion arrhythmias. Ann. NY Acad. Sci., 522, 464–477PubMedCrossRefGoogle Scholar
  60. Priori, S. G., Mantica, M., Napolitano, C. and Schwartz, P. J. (1990). Early afterdepolarizations induced in vivo by reperfusion of ischemic myocardium. Circulation, 81, 1911–1920PubMedCrossRefGoogle Scholar
  61. Saman, S., Coetzee, W. A. and Opie, L. H. (1988). Inhibition by simulated ischemia or hypoxia of delayed afterdepolarizations provoked by cyclic AMP: Significance for ischemic and reperfusion arrhythmias. J. Mot. Cell. Cardiol., 20, 91–95CrossRefGoogle Scholar
  62. Sharma, A. D., Saffitz, J. E., Lee, B. I., et al. (1983). Alpha-adrenergic mediated accumulation of calcium in reperfused myocardium. J. Clin. Invest., 72, 802–818PubMedPubMedCentralCrossRefGoogle Scholar
  63. Steenbergen, C., Murphy, E., Levy, L. and London, R. E. (1987). Elevation in cytosolic free calcium concentration early in myocardial ischemia in perfused rat heart. Circ. Res., 60, 700–707PubMedCrossRefGoogle Scholar
  64. Tani, M. and Neely, J. R. (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, 1045–1056PubMedCrossRefGoogle Scholar
  65. Thandroyen, F. T., Higginson, L. M., Opie, L. H. and Yon, E. (1986). The influence of verapamil and its isomers on vulnerability to ventricular fibrillation during acute myocardial ischemia and adrenergic stimulation in isolated rat heart. J. Mot. Cell. Cardiol., 18, 645–649CrossRefGoogle Scholar
  66. Thandroyen, F. T., McCarthy, D., Burton, K. and Opie, L. H. (1988). Ryanodine and caffeine prevent ventricular arrhythmias during acute myocardial ischemia and reperfusion in rat heart. Circ. Res., 62, 306–314PubMedCrossRefGoogle Scholar
  67. Tseng, G.-N. (1988). Calcium current restitution in mammalian ventricular myocytes is modulated by intracellular calcium. Circ. Res., 63, 468–482PubMedCrossRefGoogle Scholar
  68. Weiss, R. G., Gerstenblith, G. and Lakatta, E. G. (1987). Calcium oscillations during early reperfusion predict functional recovery and calcium gain [Abstract]. Circulation, 76 (Suppl. IV), IV-58Google Scholar

Copyright information

© Macmillan Publishers Limited 1992

Authors and Affiliations

  • L. H. Opie
  • W. A. Coetzee
  • W. T. Clusin

There are no affiliations available

Personalised recommendations