Skip to main content
SpringerLink
Log in

Pathophysiology of acute ischemia: Potential targets for antiarrhythmic drugs

  • Chapter
Myocardial Ischemia and Arrhythmia

  • 786 Accesses

Summary

The electrophysiological changes during acute myocardial ischemia show a characteristic time-dependence. The first change to be observed is a reduction in resting membrane potential and a decrease in upstroke rate of rise, amplitude, and duration of the transmembrane action potential. These changes are closely related to the loss of potassium from ischemic cells and to metabolic acidosis. At a later stage (approximately 15 min after arrest of perfusion) electrical cell-to-cell uncoupling takes place. The associated arrhythmias (ventricular tachycardia, ventricular fibrillation) are due to circus movement reentry and show an early (lA arrhythmias) and a later (1B arrhythmias) peak of incidence. Both focal and reentrant mechanisms are responsible for initiating the arrhythmias in the ischemic border zone.

The complexity of the mechanisms of antiarrhythmic drug action in acute ischemia is illustrated with three examples. In the case of lidocaine, the effect on reentrant arrhythmias is relatively well explained by the inhibitory effect on Na+channels and the consequent preferential depression of action potentials elicited from depolarized ischemic cells. Ca++entry blockade exerts multiple actions on ischemic ionic and electrical changes. Sulfonylureas are an example of drugs with a metabolic target in addition to their effect to inhibit ATP-sensitive K+ channels.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Circ 1991; 84: 1831–1851

    Google Scholar 

  2. Bayes de Luna APh, Leclercq C, Leclercq JF (1989) Ambulatory sudden death: mechanisms of production of fatal arrhythmias on the basis of data from 157 cases. Am Heart J 117: 154–161

    Google Scholar 

  3. Roelandt J, Klootwijk P, Lubsen J, et al (1984) Sudden death during long term ambulatory monitoring. Eur Heart J 5: 7–20

    PubMed  CAS  Google Scholar 

  4. Janse MJ, Kléber AG, (1981) Electrophysiological changes and ventricular arrhythmias in the early phase of regional myocardial ischemia. Circ Res 49: 1069–1081

    PubMed  CAS  Google Scholar 

  5. Janse MJ, Kléber AG (1992) Propagation of electrical activity in ischemic and infarcted myocardium as the basis of ventricular arrhythmias. J Cardiovasc Electrophysiol 3: 77–87

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  7. Downar E, Janse MJ, Durrer D (1977) The effect of acute coronary artery occlusion on subepicardial transmembrane potentials in the intact porcine heart. Circulation 56: 217–224

    PubMed  CAS  Google Scholar 

  8. Harris AS, Bisteni A, Russell RA, Brighan JC, Firestone JE (1954) Excitatory factors in ventricular tachycardia resulting from myocardial ischemia. Potassium a major excitant. Science 199: 200–203

    Google Scholar 

  9. Kléber AG (1984) Extracellular potassium accumulation in acute myocardial ischemia. J Mol Cell Cardiol 16: 389–394

    Article  PubMed  Google Scholar 

  10. Kléber AG (1983) Resting membrane potential, extracellular potassium activity, and intracellular sodium activity during acute global ischemia in isolated perfused guinea pig heart. Circ Res 52: 442–450

    PubMed  Google Scholar 

  11. Moréna H, Janse MJ, Fiolet JWT, Krieger WJG, Crijns H, Durrer D (1980) Comparison of the effects of regional ischemia, hypoxia, hyperkalemia, and acidosis on intracellular and extracellular potentials and metabolism in the isolated porcine heart. Circ Res 46: 635–646

    Google Scholar 

  12. Kléber AG, Janse MJ, Wilms-Schopman FJG, Wilde AAM, Coronel R (1986) Changes in conduction velocity during acute ischemia in ventricular myocardium of the isolated porcine heart. Circulation 73: 189–198

    Article  PubMed  Google Scholar 

  13. Kaplinsky E, Ogawa S, Balke CW, Dreifus LS (1979) Two periods of early ventricular arrhythmias in the canine acute myocardial infarction model. Circ 60: 397–394

    CAS  Google Scholar 

  14. Janse MJ, van Capelle FJL, Morsink H, Kléber AG, Wilms-Schopman FJG, Cardinal R, Nauman d’Alnoncourt C, Durrer D (1980) Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts; Evidence for two different arrhythmogenic mechanisms. Circ Res 47: 151–165

    CAS  Google Scholar 

  15. Gettes W, Reuter H (1974) Slow recovery from inactivation of inward currents in mammalian myocardial fibres. J Physiol (Lond) 240: 703–724

    CAS  Google Scholar 

  16. Lazzara R, El-Sherif N, Scherlag BJ (1975) Disorders of cellular electrophysiology produced by ischemia of the canine His bundle. Circ Res 36: 444–454

    PubMed  CAS  Google Scholar 

  17. Kodama I, Wilde AAM, Janse MJ, Durrer D, Yamada K (1984) Combined effects of hypoxia, hyperkalemia and acidosis on membrane action potential and excitability of guinea-pig ventricular muscle, J Mol Cell Cardiol 16: 246–259

    Article  Google Scholar 

  18. Janse MJ, Kléber AG, Capucci A, Coronel R, Wilms-Schopman F (1986) Electrophysiological basis for arrhythmias caused by acute ischemia. Role of the subendocardium. J Mol Cell Cardiol 18: 339–355

    Article  PubMed  CAS  Google Scholar 

  19. Pogwizd SM, Corr PB (1987) Reentrant and nonreentrant mechanisms contribute to arrhythmogenesis during early myocardial ischemia• results using three-dimensional mapping. Circ Res 61: 352–371

    PubMed  CAS  Google Scholar 

  20. Pogwizd SM, Corr PB (1990) Mechanisms underlying the development of ventricular fibrillation during early myocardial ischemia. Circ Res 66: 672–695

    PubMed  CAS  Google Scholar 

  21. Wojtczak J (1979) Contractures and increase in longitudinal resistance of cow ventricular muscle induced by hypoxia. Circ Res 44: 88–95

    PubMed  CAS  Google Scholar 

  22. Streit J (1987) Effects of hypoxia glycolytic inhibition on electrical properties of sheep cardiac Purkinje fibres. J Mol Cell Cardiol 19: 875–885

    Article  PubMed  CAS  Google Scholar 

  23. Riegger CB, Alperovich G, Kléber AG (1989) The effect of oxygen withdrawal on passive and active electrical properties of arterially perfused rabbit ventricular muscle. Circ Res 64: 532–541

    PubMed  CAS  Google Scholar 

  24. Kléber AG, Riegger CB, Janse MJ (1987) Electrical uncoupling and increase of extracellular resistance after induction of ischemia in isolated, arterially perfused rabbit papillary muscle. Circ Res 61: 271–279

    PubMed  Google Scholar 

  25. Cascio WE, Yan Gan-Xin, Kléber AG (1990) Passive electrical properties, mechanical activity and extracellular potassium in arterially perfused and ischemic rabbit ventricular muscle: effects of calcium entry blockade or hypocalcemia. Circ Res 66: 1461–1473

    PubMed  CAS  Google Scholar 

  26. Steenbergen C, Murphy E, Watts JA, London RE (1990) Correlation between cytosolic free calcium, contracture, ATP, and irreversible ischemic injury in perfused rat heart. Circ Res 66: 135–146

    PubMed  CAS  Google Scholar 

  27. Marban E, Kitakaze M, Koretsune Y, Yue DT, Chacko VP, Pike MM: Quantification of [Ca’]; in perfused hearts (1990) critical evaluation of the 5F-BAPTA and nuclear magnetic resonance method as applied to the study of ischemia and reperfusion. Circ Res 66: 1255–1267

    PubMed  CAS  Google Scholar 

  28. Wu J, McHowat J, Saffitz JE, Yamada KA, Corr PB (1993) Inhibition of gap junctional conductance by long-chain acylcarnitines and their preferential accumulation in junctional sarcolemma during hypoxia. Circ Res 72: 879–889

    PubMed  CAS  Google Scholar 

  29. Sugiura H, Toyama J, Tsuboi N, Kamiya K, Kodama I (1990) ATP directly affects junctional conductance between paired ventricular myocytes isolated from pig heart. Circ Res 66: 1095–1102

    PubMed  CAS  Google Scholar 

  30. Noma A, Tsuboi N (1987) Dependence of junctional conductance on proton, calcium and magnesium ions in cardiac paired cells of guinea pig. J Physiol (Lond) 382: 193–211

    CAS  Google Scholar 

  31. White RL, Doeller JE, Verselis VK, Wittenberg BA (1990) Gap junctional conductance between pairs of ventricular myocytes is modulated synergistically by H+ and Ca’. J Gen Physiol 95: 1061–1075

    Article  PubMed  CAS  Google Scholar 

  32. Rudy Y, Quan WeiLun (1987) A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue. Circ Res 61: 815–823

    PubMed  CAS  Google Scholar 

  33. Coronel R (1988) Distribution of extracellular potassium during myocardial ischemia. Thesis, University of Amsterdam, The Netherlands.

    Google Scholar 

  34. Coronel R, Fiolet JWT, Wilms-Schopman FJG, Schaapherder AFM, Johnson TA, Gettes LS, Janse MJ (1988) Distribution of extracellular potassium and its relation to electrophysiological changes during acute myocardial ischemia in the isolated perfused porcine heart. Circulation 77: 1125–1138

    Article  PubMed  CAS  Google Scholar 

  35. Coronel R, Fiolet JWT, Wilms-Schopman FJG, Opthof T, Schaapherder AFM, Janse MJ (1989) Distribution of extracellular potassium and electrophysiological changes during two-stage coronary ligation in the isolated, perfused porcine heart. Circulation 80: 165–177

    Article  PubMed  CAS  Google Scholar 

  36. Kléber AG, Janse MJ, van Capelle FJL (1978) Mechanism and time course of S-T and T-Q segment changes during acute regional myocardial ischemia in the pig heart determined by extracellular and intracellular recordings. Circ Res 42: 603–613

    PubMed  Google Scholar 

  37. Cascio WE, Yan GX, Kléber AG (1992) Early changes in extracellular potassium in ischemic rabbit myocardium (1992) The role of extracellular carbondioxide accumulation and diffusion. Circ Res, 70: 409–422

    PubMed  CAS  Google Scholar 

  38. Coetzee WA, Opie LH (1987) Effects of components of ischemia and metabolic inhibition on delayed afterdepolarizations in guinea pig papillary muscle. Circ Res 61: 157–165

    PubMed  CAS  Google Scholar 

  39. Wilde AAM, Kléber AG (1986) The combined effects of hypoxia, high K+, and acidosis on the intracellular sodium activity and resting potential in guinea pig papillary muscle. Circ Res 58: 249–256

    PubMed  CAS  Google Scholar 

  40. Vaughan William EM (1984) A classification of antiarrhythmic actions reassessed after a decade of new drug. J Clin Pharmacol 24: 129–147

    Google Scholar 

  41. Cardial R, Janse MJ, van Eede I, Werner G, Naumann d’Alnoncourt C, Durrer D (1981) The effect of lidocaine on intracellular and extracellular potentials, activation and ventricular arrhythmias during acute regional ischemia in the isolated porcine heart. Circ Res 49: 792–806

    Google Scholar 

  42. Carson DL, Cardinal R, Savard P, Vasseur C, Nattel S, Lambert C, Nadeau R (1986) Relationship between an arrhythmogenic action of lidocaine and its effect on excitation patterns in acutely ischemic porcine myocardium. J Cardiovasc Pharmacol 8: 126–136

    Article  PubMed  CAS  Google Scholar 

  43. Strauss HC (1990) Mechanisms of local anesthetic interaction with the sodium channel. Cardiac electrophysiology: A textbook in honor of Brian F. Hoffmann Mt Kisco, NY, Futura Publishing Co, pp. 995–1012

    Google Scholar 

  44. Wendt DJ, Starmer CF, Grant AO (1993) PH dependence of kinetics and steady-state block of cardiac sodium channels by lidocaine. Am J Physiol 264: H1588 - H1598

    PubMed  CAS  Google Scholar 

  45. Muller CA, Opie LH, Hamm CW, Peisach M, Pineda CA, Thandroyen FT (1988) Verapamil and tiapamil in prevention of ventricular fibrillation in pigs with coronary ligation. Circulation 78: 227–232

    Article  PubMed  CAS  Google Scholar 

  46. Mitani A, Kinoshita K, Fukamachi K, Sakamoto M, Kurisu K, Fukumura F, Tsuruhara Y, Nakashima A, Tokunaga K ((1992) Effects of diltiazem and noradrenaline on extracellular potassium changes in the globally ischaemic rat heart. Cardiovasc Res 26: 1040–1045

    Article  Google Scholar 

  47. Kabell G (1988) Modulation in conduction slowing in ischemic rabbit myocardium by calcium-channel activation and blockade. Circulation 77: 1385–1394

    Article  PubMed  CAS  Google Scholar 

  48. Lange R, Ingwall J, Hale SL, Alker KJ, Braunwald E, Kloner RA (1984) Preservation of high-energy phosphates by verapamil in reperfused myocardium. Circulation 70: 734–741

    Article  PubMed  CAS  Google Scholar 

  49. Amende I, Bentivegna LA, Zeind AJ, Wenzlaff P, Grossman W, Morgan JP (1992) Intracellular calcium and ventricular function. Effects of nisoldipine on global ischemia in the isovolumic coronary-perfused heart. J Clin Invest 89: 2060–2065

    Article  PubMed  CAS  Google Scholar 

  50. Richardt G, Haass M, Schomig A (1991) Calcium antagonists and cardiac noradrenaline release in ischemia. J Mol Cell Cardiol 23: 269–277

    Article  PubMed  CAS  Google Scholar 

  51. Schömig A, Rehmert G, Kurz T, Richardt G (1992) Calcium antagonism and norepinephrine release in myocardial ischemia. J Cardiovasc Pharmacol 20: S16 - S20

    Article  PubMed  Google Scholar 

  52. Schneider JA, Sperelakis N (1974) The demonstration of energy-dependence of the isoproterenol-induced transcellular Ca’ + -currents in isolated perfused guinea pig hearts — an explanation for mechanical failure of ischemic myocardium. J Surg Res 16: 389–403

    Article  PubMed  CAS  Google Scholar 

  53. Sperelakis N (1988) Regulation of calcium slow channels of cardiac muscle by cyclic nucleotides and phosphorylation. J Mol Cell Cardiol 20–11: 75–105

    Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  55. Wilde AAM, Escande D, Schumacher CA, Thuringer D, Mestre M, Fiolet JWT, Janse MJ (1990) Potassium accumulation in the globally ischemic mammalian heart. Circ Res 67: 835–843

    PubMed  CAS  Google Scholar 

  56. Kramer JTi, Lampson WG, Schaffer SW (1983) Effect of tolbutamide_ on myocardial energy metabolism. Am J Physiol 245: H313 - H319

    PubMed  CAS  Google Scholar 

  57. Rovetto MJ, Lamberton WF, Neely JR (1973) Mechanisms of glycolytic inhibition in ischemic rat heart. Circ Res 37: 742–751

    Google Scholar 

  58. Gan-Xin Yan, Kléber AG (1992) Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle Circ Res 71: 460–470

    Google Scholar 

  59. Venkatesh N, Stuart JS, Lamp ST, Alexander LD, Weiss JN (1992) Activation of ATP-sensitive K+ channels by cromakalim Effects on cellular K + loss and cardiac function in ischemic and reperfused mammalian ventricle. Circ Res, 71: 1324–1333

    PubMed  CAS  Google Scholar 

  60. Gan-Xin Yan, Yamada KA, Kléber AG, McHowat J, Corr PB (1993) Dissociation between cellular K+ loss, reduction in repolarization time, and tissue ATP levels during myocardial hypoxia and ischemia. Circ Res 72: 560–570

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, University of Bern, Bühlplatz 5, CH · 3012, Bern, Switzerland

    Prof. Dr. André G. Kléber

Authors
  1. Prof. Dr. André G. Kléber
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Abt. Innere Medizin III, Medizinische Universitätsklinik, Hugstetter Straße 55, 79106, Freiburg, Germany

    M. Zehender  & H. Just  & 

  2. Innere Medizin, Universitätskrankenhaus Eppendorf, Martinistraße 52, 20246, Hamburg, Germany

    T. Meinertz

Rights and permissions

Reprints and permissions

Copyright information

© 1994 Dr. Dietrich Steinkopff Verlag GmbH & Co. KG, Darmstadt

About this chapter

Cite this chapter

Kléber, A.G. (1994). Pathophysiology of acute ischemia: Potential targets for antiarrhythmic drugs. In: Zehender, M., Meinertz, T., Just, H. (eds) Myocardial Ischemia and Arrhythmia. Steinkopff. https://doi.org/10.1007/978-3-642-72505-0_11

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-72505-0_11

  • Publisher Name: Steinkopff

  • Print ISBN: 978-3-642-72507-4

  • Online ISBN: 978-3-642-72505-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation