Skip to main content
SpringerLink
Log in

The occurrence of oxidative stress during reperfusion in experimental animals and men

  • Reperfusion Injury: Does It Exist and Can It Be Manipulated?
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

Reperfusion is the prerequisite for the ischemic myocardium to recover its metabolic and mechanical function. However, reperfusion after a prolonged period of ischemia in the experimental animal may exacerbate, or at least accelerate, the occurrence of ischemic injury, whilst in humans at the least it is not beneficial. This entity has been called reperfusion damage, since much of the damage is believed to be caused by events occurring at the moment of reperfusion rather than by changes occurring during ischemia. The existence of reperfusion damage, however, has been questioned, and evidence in favour of the concept is sparse. At the moment the molecular events occurring at the time of reperfusion are not completely understood, and the relative importance of several proposed deleterious mechanisms is not yet established. One of the most fashionable ideas for the cause of reperfusion damage is that the function of cell membrane is modified by oxygen radicals generated at the moment of reperfusion. Evidence in favour of and against this hypothesis is described in detail in the present article.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ferrari R, Curello S, Cargnoni A, et al. Metabolic changes during post-ischaemic reperfusion. J Mol Cell Cardiol 1988;20, Suppl II:119–133.

    Article  PubMed  CAS  Google Scholar 

  2. Hearse DJ. Reperfusion of ischaemic myocardium. J Mol Cell Cardiol 1977;9:607–616.

    Google Scholar 

  3. GISSI Study. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986;1: 397–401.

    Google Scholar 

  4. Yusuf S, Collins R, Peto R, et al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: Overview of results on mortality, reinfarction and side effects from 33 controlled randomized trials. Eur Heart J 1984;6:556–585.

    Google Scholar 

  5. Braunwald E, Kloner RA. Myocardial reperfusion: A double-edged sword. J Clin Invest 1985;76:1713–1719.

    Article  PubMed  CAS  Google Scholar 

  6. Poole-Wilson PA. Reperfusion damage in heart muscle: Still unexplained but with new clinical relevance. Clin Physiol 1987;7:439–453.

    Article  PubMed  CAS  Google Scholar 

  7. Thompson JA, Hess ML. The oxygen free radical system: A fundamental mechanism in the production of myocardial necrosis. Prog Cardiovasc Dis 1986;6:449–462.

    Article  Google Scholar 

  8. Misra HP, Fridovich I. The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 1972;247:3170–3175.

    PubMed  CAS  Google Scholar 

  9. Marklund SL, Grankvis K, Taijeda F. Oxy-radicals in the toxicity of cellular toxins. In: Greenvald RA, Goh G, eds. Oxy-radicals and their scavenger system, Amsterdam: Elsevier, 1983:6–104.

    Google Scholar 

  10. Misra HP, Fridovich I. The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 1972;247:6960–6962.

    PubMed  CAS  Google Scholar 

  11. McCord JM, Fridovich I. Superoxide dismutase, and enzyme function for erythrocuprein. J Biol Chem 1969;244: 6049–6055.

    PubMed  CAS  Google Scholar 

  12. Freeman BA, Crapo JD. Biology of disease, free radicals and tissue injury. Lab Invest 1982;47:412–426.

    PubMed  CAS  Google Scholar 

  13. Kontos HA. Oxygen radicals in cerebral vascular injury. Circ Res 1985;57:508–516.

    PubMed  CAS  Google Scholar 

  14. Halliwell B, Gutteridge JMC. Oxygen toxicity, oxygen radicals, transition metals disease. Biochem J 1984;219:1–14.

    PubMed  CAS  Google Scholar 

  15. Weiss SJ. Oxygen, ischemia and inflammation. Acta Physiol Scand 1986;548(Suppl.):9–37.

    CAS  Google Scholar 

  16. Curello S, Ceconi C, Medici D, Ferrari R. Oxidative stress during myocardial ischaemia and reperfusion: Experimental and clinical evidences. J Appl Cardiol 1986;1:311–327.

    CAS  Google Scholar 

  17. Ferrari R, Ceconi C, Curello S, et al. Oxygen-mediated myocardial damage during ischemia and reperfusion: Role of the cellular defences against oxygen toxicity. J Mol Cell Cardiol 1985;17:937–945.

    Article  PubMed  CAS  Google Scholar 

  18. Ferrari R, Curello S, Ceconi C, et al. Alterations of glutathione status during myocardial ischaemia and reperfusion. In: Singel PK, ed. Oxygen radicals in the pathophysiology of heart disease. Boston: Kluwer Academic, 1988:145–160.

    Google Scholar 

  19. Ferrari R, Ceconi C, Curello S, et al. Oxygen free radicals and reperfusion injury: The effects of ischaemia and reperfusion on the cellular ability to neutralize oxygen toxicity. J Mol Cell Cardiol 1986;18:67–69.

    Article  PubMed  CAS  Google Scholar 

  20. Ferrari R, Ceconi C, Curello S, et al. Intracellular effects of myocardial ischaemia and reperfusion: Role of calcium and oxygen. Eur Heart J 1986;7:3–12.

    PubMed  CAS  Google Scholar 

  21. Rao PS, Cochen MV, Mueller HS. Production of free radicals and lipid peroxides in early experimental myocardial ischaemia. J Mol Cell Cardiol 1983;15:713–716.

    Article  PubMed  CAS  Google Scholar 

  22. Turner JF, Boveris A. Generation of superoxide anion by NADH dehydrogenase of bovine heart mitochondria. Biochem J 1980;1291:421–430.

    Google Scholar 

  23. Ferrari R, Bongrani S, Cucchini F, et al. Effects of molecular oxygen and calcium on heart metabolism during reperfusion. In: Bertrand ME, ed. Coronary arterial spasm. 1982:46–59.

  24. Nohl H. The biochemical mechanism of the formation of reactive oxygen species in heart mitochondria. In: Caldarera CM, Harris P, es. Advances in studies on heart metabolism. Bologna: Cooperativa Libraria Universitaria Editrice, 1982:413–421.

    Google Scholar 

  25. Otani H, Tanaka H, Inove T, et al. In vitro studies on contribution of oxidative metabolism of isolated rabbit heart mitochondria to myocardial reperfusion injury. Circ Res 1984;55:168–172.

    PubMed  CAS  Google Scholar 

  26. Egan RW, Paxton J, Kuehl FAJr. Mechanisms for the irreversible self deactivation of prostaglandin synthetase. J Biol Chem 1976;251:7329–7335.

    PubMed  CAS  Google Scholar 

  27. Chambers DE, Parks DA, Patterson G, et al. Xanthine oxidase as a source of free radical in myocardial ischaemia. J Mol Cell Cardiol 1985;17:145–152.

    Article  PubMed  CAS  Google Scholar 

  28. Werns SW, Shea MJ, Mitsos SE, et al. Reduction of the size of infarction by allopurinol in the ischaemic reperfused canine heart. Circulation 1986;73:518–524.

    PubMed  CAS  Google Scholar 

  29. Akizuki S, Yoshida S, Chambers DE, et al. Infarct size limitation by the xanthine oxidase inhibitor, allopurinol, in closed chest dogs with small infarcts. Cardiovasc Res 1985;19:686–692.

    Article  PubMed  CAS  Google Scholar 

  30. Arnold WL, DeWall RH, Keydi P, Eward HH. The effect of allopurinol on the degree of early myocardial ischaemia. Am Heart J 1985;99:614–624.

    Article  Google Scholar 

  31. Parratt JR, Wainwright CL. Failure of allopurinol and a spin-trapping agent N-t-alpha-phenyl nitrone to modify significantly ischaemia and reperfusion-induced arrhythmias. Br J Pharmacol 1987;91:49–59.

    PubMed  CAS  Google Scholar 

  32. Podzuweit J, Braun W, Muller A, Schaper W. Arrhythmias and infarction in the ischemic pig heart are not mediated by xanthine-derived free oxygen radicals. Circulation 1986; 74(Suppl. II):II-346.

    Google Scholar 

  33. Kehrer JP, Piper H, Sies H. Xanthine oxidase is not responsible for reoxygenation injury in isolated-perfused rat heart. Free Rad Res Comm 1987;3:69–78.

    Article  CAS  Google Scholar 

  34. Al-Khalidi USA, Chaglassian TH. The species distribution of xanthine oxidase. Biochem J 1965;97:318–320.

    PubMed  CAS  Google Scholar 

  35. Downey JM, Hearse DJ, Yellon DM. The role of xanthine oxidase during myocardial ischaemia in several species including man. J Mol Cell Cardiol 1988;20(Suppl. II):55–63.

    Article  PubMed  CAS  Google Scholar 

  36. Downey J, Chambers D, Miura T, et al. Allopurinol fails to limit infarct size in a xanthine oxidase-deficient species. Circulation 1986;74(Suppl. II):372.

    Google Scholar 

  37. Enhgerson TD, McKelvey TG, Rhynie DB, et al. Conversion of xanthine dehydrogenase to oxidase in ischaemic rat tissue. J Clin Invest 1987;79:2564–2570.

    Google Scholar 

  38. Weiss SJ, Lampert MB, Test ST. Long-lived oxidants generated by human neutrophils: Characterization and bioactivity. Science 1983;222:625–628.

    Article  PubMed  CAS  Google Scholar 

  39. Romson J, Hook B, Kunel S, et al. Reduction in the extent of ischaemic myocardial injury by neutrophil depletion in the dog. Circulation 1983;67:1016–1023.

    PubMed  CAS  Google Scholar 

  40. Zweier L, Flaherty JT, Weisfeldt ML. Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci USA 1987;84:1404–1407.

    Article  PubMed  CAS  Google Scholar 

  41. Luber JM, Rao PS, Crowder MS. Identification of free radicals produced during myocardial ischaemia and reperfusion using electron paramagnetic resonance spectroscopy and high precision liquid chromatography. J Thorac Cardiovasc Surg, in press.

  42. Arroyo CM, Kramer JH, Dickens BF, Weglicki WB. Identification of free radicals in myocardial ischemia/reperfusion by spin trapping with nitron DMPO. FEBS Lett 1987; 221:101–104.

    Article  PubMed  CAS  Google Scholar 

  43. Arroyo CM, Kramer JH, Leiboff RH, et al. Spin trapping of oxygen and carbon-centered free radicals in ischaemic canine myocardium. Free Rad Biol Med 1987;3:313–316.

    Article  PubMed  CAS  Google Scholar 

  44. Garnck PB, Davies MJ, Hearse DJ, Slater TF. Direct detection of free radicals in the reperfused rat heart using electron spin resonance spectroscopy. Circ Res 1987;61: 757–760.

    Google Scholar 

  45. Bolli R, Patel BS, Jeroudi MO, et al. Demonstration of free radical generation in “stunned” myocardium of intact dogs with use of the spin trap alpha-phenyl n-tert-butyl nitrone. J Clin Invest 1988;82:476–485.

    Article  PubMed  CAS  Google Scholar 

  46. Limm W, Mugiishi M, Piette LH, Namara JJ. Quantitative assessment of free radical generation during ischemia and reperfusion in the isolated rabbit heart (abstract). Proc Fourth Int Congr Oxygen Radicals, La Jolla, CA 1987; 123–125.

  47. Nakazawa H, Ban K, Okino H, et al. The quantification of free radicals in myocardium obtained by super rapid sampling and freezing. Circulation 1986;74(Suppl. 433).

    Google Scholar 

  48. Nakazawa H, Ichimori K, Shinozaki Y, et al. Is superoxide demonstration by electro-spin resonance spectroscopy really superoxide? Am J Physiol 1988;255:H213-H215.

    PubMed  CAS  Google Scholar 

  49. Ceconi C, Curello S, Cargnoni A, et al. The role of glutathione status in the protection against ischaemic and reperfusion damage: Effects of N-acetyl cysteine. J Mol Cell Cardiol 1988;20:5–13.

    Article  PubMed  CAS  Google Scholar 

  50. Ferrari R, Ceconi C, Curello S, et al. Oxygen utilization and toxicity at myocardial level. In: Benzi G, Packer L, Siliprandi N, eds. Biochemical aspects of physical exercise. Amsterdam: Elsevier, 1986:145–156.

    Google Scholar 

  51. Meister A. Methods for selective modification of glutathione metabolism and study of glutathione transport. In: Meister A, ed. Methods in enzymology. New York: Academic Press, 1985;571–585.

    Google Scholar 

  52. Meister A, Anderson ME. Glutathione (review). Ann Rev Biochem 1983;52:711–760.

    Article  PubMed  CAS  Google Scholar 

  53. Chance B, Sies M, Boveris A. Hydroperoxide metabolism in mammalian organs (review). Physiol Rev 1979;59:527–605.

    PubMed  CAS  Google Scholar 

  54. Gaudel Y, Duvelleroy MA. Role of oxygen radicals in cardiac injury due to reoxygenation. J Mol Cell Cardiol 1984;16:459–470.

    Article  Google Scholar 

  55. Guarnieri C, Flamigni F, Caldarera CM. Role of oxygen in the cellular damage induced by re-oxygenation of hypoxic heart. J Mol Cell Cardiol 1980;12:797–808.

    Article  PubMed  CAS  Google Scholar 

  56. Meerson FZ, Kagan VE, Kozlov Yu P, et al. The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of the heart. Basic Res Cardiol 1982;77:465–485.

    Article  PubMed  CAS  Google Scholar 

  57. Gutteridge JMC, Quinlan GJ. Malondialdehyde formation from lipid peroxides in the thiobarbituric acid test: The role of lipid radicals, iron salts, and metal chelators. J Appl Biochem 1983;5:293–299.

    PubMed  CAS  Google Scholar 

  58. Dormandy TL. Free radical oxidation and antioxidants. Lancet 1978;1:647–650.

    Article  PubMed  CAS  Google Scholar 

  59. Ceconi C, Cargnoni A. Pasini E, et al. Evaluation of phospholipid peroxidation as malondialdehyde during myocardial ischaemic and reperfusion injury. Am J Physiol, in press.

  60. Ceconi C, Pasini E, Benigno M, et al. Heart lipid peroxidation: HPLC versus TBA for determination of malondialdehyde. International Teach-in for Promoting Scientific Basis of Cardiology, Roma, 23–25 October, 1989.

  61. Curello S, Ceconi C, Bigoli C, et al. Change in the cardiac glutathione status after ischaemia and reperfusion. Experientia 1985;41:42–43.

    Article  PubMed  CAS  Google Scholar 

  62. Ferrari R, Ceconi C, Curello S, et al. Molecular events occurring during post-ischaemic reperfusion. In: Dhalla NS, Innes IR, Beamish RE, eds. Myocardial ischaemia, Boston: Nijhoff Publishing, 1987;67–84.

    Google Scholar 

  63. Larsson A, Orrenius S, Holmegren A, eds. Functions of glutathione: Biochemical, physiological, toxicological and clinical aspects, New York: Raven Press, 1983.

    Google Scholar 

  64. Mc Intyre TM, Curthoys NP. The interorgan metabolism of glutathione. Int J Biochem 1980;12:545–551.

    Article  CAS  Google Scholar 

  65. Mannervik B, Axelsson K. Role of cytoplasmic thioltransferase in cellular regulation by thiol-disulphide interchange. Biochem J 1980;190:125–130.

    PubMed  CAS  Google Scholar 

  66. Meister A, Tate SS. Glutathione and related-glutamil compounds: Biosynthesis and utilization. Ann Rev Biochem 1976;45:559–564.

    Article  PubMed  CAS  Google Scholar 

  67. Ferrari R, Visioli O, Caldarera CM, Nayler WG. Vitamin E and the heart: Possible role as antioxidants. Acta Vitamin et Enzymol 1982;5:11–22.

    Google Scholar 

  68. Curello S, Ceconi C, Cargnoni A, et al. Improved procedure for determining glutathione plasma as an index of myocardial oxidative stress. Clin Chem 1987;33/8:1448–1449.

    Google Scholar 

  69. Adams JP, Lauterburg BM, Mitchell JR. Plasma glutathione and glutathione disulfide in rat: Regulation and response to oxidative stress. J Pharmacol Exp Ther 1983:227;749–754.

    PubMed  CAS  Google Scholar 

  70. Ishikawa H, Sies H. Cardiac transport of glutathione disulfide and s-conjugate. J Biol Chem 1984;259:333–342.

    Google Scholar 

  71. Ferrari R, Alfieri O, Curello S, et al. Occurrence of oxidative stress during reperfusion of the human heart. Circulation 1990;81(1):201–211.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cattedra di Cardiologia, Universita' degli Studi di Brescia, Brescia, Italy

    Roberto Ferrari, Claudio Ceconi, Salvatore Curello, Anna Cargnoni, Evasio Pasini & Odoardo Visioli

Authors
  1. Roberto Ferrari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio Ceconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Salvatore Curello
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Cargnoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Evasio Pasini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Odoardo Visioli
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferrari, R., Ceconi, C., Curello, S. et al. The occurrence of oxidative stress during reperfusion in experimental animals and men. Cardiovasc Drug Ther 5 (Suppl 2), 277–287 (1991). https://doi.org/10.1007/BF00054749

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00054749

Key Words

Search

Navigation