Preconditioning: An Early Protective Response to Myocardial Ischaemia

  • Agnes Vegh
  • Laszlo Szekeres
  • James R. Parratt


Recently there has been a great deal of interest in the concept that myocardial cells are capable of rapidly adapting to brief periods of stress, such as ischaemia, in a manner that is protective against longer periods of the same form of stress. The term ‘preconditioning’ was first used by Murry et al. (1986) to describe the effects of multiple brief coronary artery occlusions on infarct size produced by a subsequent, prolonged occlusion. They found that if dogs were preconditioned by brief (5 min) episodes of ischaemia, each separated by 5 min periods of reperfusion or recovery, and were then subjected to a sustained (40 min) reocclusion without subsequent reperfusion, then infarcts in the preconditioned hearts were much smaller (by up to 75%) than those in the controls at any given level of coronary collateral flow.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aksnes, G., Ellingsen, O., Rutlen, D. L. and Ilebekk, A. (1989). Myocardial K+ repletion and rise in contractility after brief ischemic periods in the pig. J. Mol. Cell. Cardiol., 21, 681–690PubMedCrossRefGoogle Scholar
  2. Barber, M. J. (1983). Effect of time interval between repeated brief coronary artery occlusions on arrhythmias, electrical activity and myocardial blood flow. J. Am. Coll. Cardiol., 2, 699–705PubMedCrossRefGoogle Scholar
  3. Bolli, R. (1988). Oxygen-derived free radicals and postischemic myocardial dysfunction (‘Stunned Myocardium’). J. Am. Coll. Cardiol., 12, 239–249PubMedCrossRefGoogle Scholar
  4. Bolli, R. (1990). Mechanism of myocardial ‘stunning’. Circulation, 82, 723–738PubMedCrossRefGoogle Scholar
  5. Belli, R., Patel, B. S., Zhu, W. X., O’Neill, P. G., Charlat, M. L. and Roberts, R. (1987b). The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction. Am. J. Physiol., 253, H1372-H1380Google Scholar
  6. Bolli, R., Zhu, W. X., Hartley, C. J., Michael, L. H., Repine, J., Hess, M. L., Kukreja, R. C. and Roberts, R. (1987a). Attenuation of dysfunction in the postischemic ‘stunned’ zyocardium by dimethylthiourea. Circulation, 76, 458–468PubMedCrossRefGoogle Scholar
  7. Brown, A. M. and Malliani, A. (1971). Spinal sympathetic reflexes initiated by coronary receptors. J. Physiol., 212, 685–705PubMedPubMedCentralCrossRefGoogle Scholar
  8. Charlat, M. L., O’Neill, P. G., Egan, J. M., Abernethy, D. R., Michael, L. H., Myers, M. L., Roberts, R. and Bolli, R. (1987). Evidence for a pathogenetic role of xanthine oxidase in the ‘stunned’ myocardium. Am. J. Physiol., 252, H566-H577PubMedGoogle Scholar
  9. Ciuffo, A. A., Ouyang, P., Becker, L. C., Levin, L. and Weisfeldt, M. L. (1985). Reduction of sympathetic inotropic response after ischaemia in dogs. Contributor to stunned myocardium. J. Clin. Invest., 75, 1504–1509PubMedPubMedCentralCrossRefGoogle Scholar
  10. Coker, S. J. and Parratt, J. R. (1983a). Prostacyclin-antiarrhythmic or arrhythmogenic? Comparison of the effects of intravenous and intracoronary prostacyclin and ZK 36374 during coronary artery occlusion and reperfusion in anaesthetised greyhounds. J. Cardiovasc. Pharmacol., 5, 557–567PubMedCrossRefGoogle Scholar
  11. Coker, S. J. and Parratt, J. R. (1983b). Effects of dazoxiben on arrhythmias and ventricular fibrillation induced by coronary artery occlusion and reperfusion in anaesthetised greyhounds. Br. J. Clin. Pharmacol., 15, 87–96CrossRefGoogle Scholar
  12. Coker, S. J. and Parratt, J. R. (1984). The effects of nafazatrom on arrhythmias and prostanoid release during coronary artery occlusion and reperfusion in anaesthetised greyhounds. J. Mol. Cell. Cardiol., 16, 43–52PubMedCrossRefGoogle Scholar
  13. Coker, S. J., Parratt, J. R., Ledingham, I. McA. and Zeitlin, I. J. (1981a). Thromboxane and prostacyclin release from ischaemic myocardium in relation to arrhythmias. Nature, 291, 323–324PubMedCrossRefGoogle Scholar
  14. Coker, S. J., Parratt, J. R., Ledingham, 1. McA. and Zeitlin, I. J. (1981b). Aspirin inhibits the early myocardial release of thromboxane B2 and ventricular ectopic activity following acute coronary artery occlusion in dogs. Br. J. Pharmacol., 72, 593–595PubMedPubMedCentralCrossRefGoogle Scholar
  15. Fagbemi, O. and Parratt, J. R. (1984). Antiarrhythmic actions of adenosine in the early stages of experimental myocardial ischaemia. Ear. J. Pharmacol., 100, 243–244CrossRefGoogle Scholar
  16. Farber, N. E. and Gross, G. J. (1990). Prostaglandin redirection by thromboxane synthetase inhibition: Attenuation of myocardial stunning in canine heart. Circulation, 81, 369–380PubMedCrossRefGoogle Scholar
  17. Farber, N. E., Pieper, G. M. and Gross, G. J. (1988). Lack of thromboxane A2 involvement in the postischemic recovery of the stunned myocardium. Circulation, 78, 450–461PubMedCrossRefGoogle Scholar
  18. Fleet, W. F., Johnson, T. A., Graebner, C. A. and Gettes, L. S. (1985). Effect of serial brief ischemic episodes on extracellular K+, pH, and activation in the pig. Circulation, 72, 922–932PubMedCrossRefGoogle Scholar
  19. Fleming, I., Gray, G. A., Julou-Schaeffer, G., Parratt, J. R. and Stoclet, J. C. (1990). Incubation with endotoxin activates the L-arginine pathway in vascular tissue. Biochem. Biophys. Res. Commun., 171, 562–568PubMedCrossRefGoogle Scholar
  20. Förster, W. (1976). Prostaglandins and prostacyclin precursors as endogenous antiarrhythmic principles of the heart. Acta Biol. Med. Germ., 35, 1101–1112PubMedGoogle Scholar
  21. Gross, G. J., Farber, N. E., Hardman, H. F. and Warltier, D. C. (1986). Beneficial actions of superoxide dismutase and catalase in stunned myocardium of dogs. Am. J. Physiol., 250, H372-H377PubMedGoogle Scholar
  22. Gryglewski, R. J. and Stock, G. (Eds), (1987). Prostacyclin and Its Stable Analogue Iloprost. Springer, BerlinGoogle Scholar
  23. Harris, A. G. (1950). Delayed development of ventricular ectopic rhythms following experimental coronary occlusion. Circulation, 1, 1318–1326PubMedCrossRefGoogle Scholar
  24. Henrichs, K. J., Matsuoka, H. and Schaper, J. (1987). Influence of repetitive coronary occlusions on myocardial adenine nucleosides, high energy phosphates and ultrastructure. Basic Res. Cardiol., 82, 557–565PubMedCrossRefGoogle Scholar
  25. Hill, J. L. and Gettes, L. E. (1980). Effect of acute coronary artery occlusions on local myocardial extracellular K+ activity in swine. Circulation, 61, 768–778PubMedCrossRefGoogle Scholar
  26. Hirche, H., Friedrich, R., Kebbel, U., McDonald, F. and Zylka, V. (1982). Early arrhythmias, myocardial extracellular potassium and pH. In Parratt, J. R. (Ed), Early Arrhythmias Resulting from Myocardial Ischaemia. Macmillan, London, pp. 113–124CrossRefGoogle Scholar
  27. Hoffmeister, H. M., Mauser, M. and Schaper, W. (1986). Repeated short periods of regional myocardial ischemia: Effect on local function and high energy phosphate levels. Basic Res. Cardiol., 81, 361–372PubMedCrossRefGoogle Scholar
  28. Homans, D. C., Sublett, E., Dai, X. Z. and Bache, R. J. (1986). Persistence of regional left ventricular dysfunction after exercise-induced myocardial ischaemia. J. Clin. Invest., 77, 66–73PubMedPubMedCentralCrossRefGoogle Scholar
  29. Jennings, R. B., Reimer, K. A., Hill, M. L. and Mayser, S. E. (1981). Total ischemia in dog hearts, in vitro: I. Comparison of high energy phosphate production, utilization and depletion and of adenine nucleotide catabolism in total ischemia in vitro vs severe ischemia in vivo. Circ. Res., 49, 892–900PubMedCrossRefGoogle Scholar
  30. Jones, R. N., Reimer, K. A., Hill, M. L. and Jennings, R. B. (1982). Effect of hypothermia on changes in high-energy phosphate production and utilization in total ischemia. J. Mol. Cell. Cardiol., 14 (Suppl. 3), 123–130PubMedCrossRefGoogle Scholar
  31. Julou-Schaeffer, G., Gray, G. A., Fleming, I., Schott, C., Parratt, J. R. and Stoclet, J-C. (1990). Loss of vascular responsiveness induced by endotoxin involves the L-arginine pathway. Am. J. Physiol., 259, H1038-H1043PubMedGoogle Scholar
  32. Kloner, R. A., Ellis, S. G., Lange, R. and Braunwald, E. (1983). Studies of experimental coronary artery reperfusion: Effects on infarct size, myocardial function, biochemistry, ultrastructure and microvascular damage. Circulation, 68 (Suppl. 1), I-8-I-15Google Scholar
  33. Komori, S., Parratt, J. R., Szekeres, L. and Vegh, A. (1990). Preconditioning reduces the severity of ischaemia and reperfusion-induced arrhythmias in both anaesthetised rats and dogs. J. Physiol., 423, 16PGoogle Scholar
  34. Li, G. C., Vasquez, J. A., Gallagher, K. P. and Lucchesi, B. R. (1990). Myocardial protection with preconditioning. Circulation, 82, 609–619PubMedCrossRefGoogle Scholar
  35. Malliani, A., Schwartz, P. J. and Zanchetti, A. (1969). Reflex activity of single preganglionic sympathetic fibres during coronary occlusion. Experientia, 25, 152–153PubMedCrossRefGoogle Scholar
  36. Marshall, R. J. and Parratt, J. R. (1980). The early consequences of myocardial ischaemia and their modification. J. Physiol (Paris), 76, 699–715Google Scholar
  37. Meesmann, W. (1982). The possible role of the sympathetic nervous system in the genesis of early post-ischaemia arrhythmias. In Parratt, J. R. (Ed.), Early Arrhythmias Resulting from Myocardial Ischaemia. Macmillan, London, pp. 139–151CrossRefGoogle Scholar
  38. Myers, M. L., Bolli, R., Lekich, R. F., Hartley, C. J. and Roberts, R. (1985). Enhancement of recovery of myocardial function by oxygen free-radical scavengers after reversible regional ischaemia. Circulation, 75, 915–921CrossRefGoogle Scholar
  39. Myers, M. L., Bolli, R., Lekich, R. G., Hartley, C. J. and Roberts, R. (1986). N-2-Mercaptopropionylglycine improves recovery of myocardial function following reversible regional ischaemia. J. Am. Coll. Cardiol., 8, 1161–1168PubMedCrossRefGoogle Scholar
  40. Murry, C. E., Jennings, R. B. and Reimer, K. A. (1986). Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation, 74, 1124–1136PubMedCrossRefGoogle Scholar
  41. Murry, C. E., Richard, V. J., Reimer, K. A. and Jennings, R. B. (1990). Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ. Res., 66, 913–931PubMedCrossRefGoogle Scholar
  42. Parratt, J. R. (1987). Reperfusion arrhythmias, platelet-vessel wall interactions and endogenous antiarrhythmic substances. In Papp, J. G. (Ed.), Cardiovascular Pharmacology ’87: Results, Concepts and Perspectives. Akademiai Kiado, Budapest, pp. 3–16Google Scholar
  43. Parratt, J. R., Boachie-Ansah, G., Kane, K. A. and Wainwright, C. L. (1988). Is adenosine an endogenous antiarrhythmic agent under conditions of myocardial ischaemia? In Paton, D. M. (Ed.), Adenosine and Adenine Nucleotides. Taylor and Francis, London, pp. 157–166Google Scholar
  44. Parratt, J. R., Campbell, C. and Fagbemi, O. (1981). Catecholamines and early post-infarction arrhythmias: the effects of alpha and beta-adrenoceptor blockade. In Delius, W., Gerlach, E., Grobecker, H. and Kubler, W. (Eds), Catecholamines and the Heart. Springer, Berlin, pp. 269–284CrossRefGoogle Scholar
  45. Puett, D. W., Forman, M. B., Cates, C. U., Wilson, B. H., Hande, K. R., Friesinger, G. C. and Virmani, R. (1987). Oxypurinol limits myocardial stunning but does not reduce infarct size after reperfusion. Circulation, 76, 678–686PubMedCrossRefGoogle Scholar
  46. Podzuweit, T., Binz, K.-H., Nennstiel, P. and Flaig, W. (1989). The anti-arrhythmic effects of myocardial ischaemia. Relation to reperfusion arrhythmias? Cardiovasc. Res., 23, 81–90PubMedCrossRefGoogle Scholar
  47. Przyklenk, K. and Kloner, R. A. (1986). Superoxide dismutase plus catalase improve contractile function in the canine model of the ‘stunned’ myocardium. Circ. Res., 58, 148–156PubMedCrossRefGoogle Scholar
  48. Schott, R. J. and Schaper, W. (1989). Effects of transient coronary occlusion: experience with myocardial stunning and preconditioning. Israel J. Med. Sci., 25, 479–482PubMedGoogle Scholar
  49. Schwartz, P. J. and Stone, H. L. (1980). Left stellectomy in the prevention of ventricular fibrillation caused by acute myocardial ischaemia in conscious dogs with anterior myocardial infarction. Circulation, 62, 1256–1265PubMedCrossRefGoogle Scholar
  50. Shiki, K. and Hearse, D. J. (1987). Preconditioning of ischemic myocardium: reperfusion-induced arrhythmias. Am. J. Physiol., 253, H1470-H1476PubMedGoogle Scholar
  51. Szekeres, L., Blazsovszky, M., Pataricza, J. and Udvary, E. (1984). On the mechanism and drug treatment of early arrhythmias due to local myocardial ischemia. In Szekeres, L., Papp, J. Gy. and Takats, I. (Eds), Pathomechanisms and Prevention of Sudden Cardiac Death Due to Coronary Insufficiency. Akad. Kiado, Budapest, pp. 3–11Google Scholar
  52. Szekeres, L., Boros, E., Pataricza, J. and Udvary, E. (1986). Sympathetic neural mechanisms in cardiac arrhythmias. J. Mol. Cell Cardiol., 18, 369–373PubMedCrossRefGoogle Scholar
  53. Vegh, A., Szekeres, L. and Parratt, J. R. (1990a). Preconditioning of the ischaemic myocardium: Role of the cyclooxygenase pathway. Br. J. Pharmacol., 99, 19PGoogle Scholar
  54. Vegh, A., Szekeres, L. and Parratt, J. R. (1990b). Protective effects of preconditioning of the ischaemic myocardium involve cyclo-oxygenase products. Cardiovasc. Res., 24, 1020–1022PubMedCrossRefGoogle Scholar
  55. Vegh, A., Szekeres, L. and Parratt, J. R. (1991). Preconditioning of the ischaemic myocardium: effect of N’nitro-L-arginine methyl ester (L-NAME). Br. J. Pharmacol., 102, 124PGoogle Scholar
  56. Wainwright, C. L. and Parratt, J. R. (1988). An antiarrhythmic effect of adenosine during myocardial ischaemia and reperfusion. Eur. J. Pharmac., 145, 183–194CrossRefGoogle Scholar
  57. Wainwright, C. L., van Belle, H. and Parratt, J. R. (1990). The antifibrillatory effects of R75231, a specific nucleoside transport inhibitor. J. Mol. Cell. Cardiol., 22, (Suppl. III), S77Google Scholar

Copyright information

© Macmillan Publishers Limited 1992

Authors and Affiliations

  • Agnes Vegh
  • Laszlo Szekeres
  • James R. Parratt

There are no affiliations available

Personalised recommendations