Skip to main content
SpringerLink
Log in

Myocardial ischemia and reperfusion: The role of oxygen radicals in tissue injury

  • Focused Section on Acute Myocardial Ischemia and Infarction
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Summary

Thrombolytic therapy has gained widespread acceplance as a means of treating coronary artery thrombosis in patients with acute myocardial infarction. Although experimental data have demonstrated that timely reperfusion limits the extent of infarction caused by regional ischemia, there is growing evidence that reperfusion is associated with an inflammatory response to ischemia that exacerbates the tissue injury. Ischemic myocardium releases archidonate and complement-derived chemotactic factors, e.g., leukotriene B4 and C5a, which attract and activate neutrophils. Reperfusion of ischemic myocardium accelerates the influx of neutrophils, which release reactive oxygen products, such as superoxide anion and hydrogen peroxide, resulting in the formation of a hydroxyl radical and hypochlorous acid. The latter two species may damage viable endothelial cells and myocytes via the peroxidation of lipids and oxidation of protein sulfhydryl groups, leading to perturbations of membrane permeability and enzyme function. Neutrophil depletion by antiserum and inhibition of neutrophil function by drugs, e.g., ibuprofen, prostaglandins (prostacyclin and PGE1), or a monoclonal antibody, to the adherence-promoting glycoprotein Mo-1 receptor, have been shown to limit the extent of canine myocardial injury due to coronary artery occlusion/reperfusion. Recent studies have challenged the hypothesis that xanthine-oxidase-derived oxygen radicals are a cause of reperfusion injury. Treatment with allopurinol or oxypurinol may exert beneficial effects on ischemic myocardium that are unrelated to the inhibition of xanthine oxidase. Furthermore, the human heart may lack xanthine oxidase activity. Further basic research is needed, therefore, to clarify the importance of xanthine oxidase in the pathophysiology of reperfusion injury. Current data are highly suggestive of a deleterious role of the neutrophil in organ reperfusion and justify consideration of the clinical investigation of neutrophil inhibitors in patients receiving thrombolytic agents during the evolution of an acute myocardial infarction.

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. DeWood, MA, Spores, J, Notske, R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897–902.

    Google Scholar 

  2. Topol, EJ. Advances in thrombolytic therapy for acute myocardial infarction. J Clin Pharmacol 1987;27:735–745.

    Google Scholar 

  3. Hearse, DJ, Humphrey, SM, Bullock, GR. The oxygen paradox and the calcium paradox. Two facets of the same problem? J Mol Cell Cardiol 1978;10:641–648.

    Google Scholar 

  4. 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.

    Google Scholar 

  5. Hess, ML, Manson, NH. Molecular oxygen: Friend and foe. The role of the oxygen free radical system in the calcium paradox, the oxygen paradox and ischemia/reperfusion injury. J Mol Cell Cardiol 1984;16:969–985.

    Google Scholar 

  6. McCord, JM. Oxygen-derived free radicals in post ischemic tissue injury. N Engl J Med 1985;312:159–163.

    Google Scholar 

  7. Lucchesi, BR, Mullane, KM. Leukocytes and ischemia-induced myocardial injury. Ann Rev Pharmacol Toxicol 1986;26:201–204.

    Google Scholar 

  8. Southorn, PA, Powis, G. Free radicals in medicine: I. Chemical nature and biologic reactions. Mayo Clin Proc 1988; 63:381–389.

    Google Scholar 

  9. Southorn, PA, Powis, G. Free radicals in medicine: II. Involvement in human disease. Mayo Clin Proc 1988;63:390–408.

    Google Scholar 

  10. Halliwell, B, Gutteridge, JMC. The importance of free radicals and catalytic metal ions in human diseases. Molec Aspects Med 1985;8:89–193.

    Google Scholar 

  11. Halliwell, B. Oxidants and human disease: Some new concepts. FASEB J 1987;1:358–364.

    Google Scholar 

  12. Biemond, P, VanEijk, HG, Swaak, AJG, et al. Iron mobilization from ferritin by O2 derived from stimulated polymorphonuclear leukocytes. Possible mechanism in inflammation disease. J Clin Invest 1984;73:1576–1579.

    Google Scholar 

  13. Gutteridge, JMC. Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett 1986;201:291–295.

    Google Scholar 

  14. Noronha-Dutra, AA, Steen, EM. Lipid peroxidation as a mechanism of injury in cardiac myocytes. Lab Invest 1982;47:346–353.

    Google Scholar 

  15. Toth, KM, Clifford, DP, Berger, EM, et al. Intact human erythrocytes prevent hydrogen peroxide-mediated damage to isolated perfused rat lungs and cultured bovine pulmonary artery endothelial cells. J Clin Invest 1984;74:292–295.

    Google Scholar 

  16. Agar, NS, Sadrzadeh, SMH, Hallaway, PE, et al. Erythrocyte catalase: A somatic oxidant defense. J Clin Invest 1986; 77:319–321.

    Google Scholar 

  17. Winterbourn, CC, Stern, A. Human red cells scavenge extracellular hydrogen peroxide and inhibit formation of hypochlorous acid and hydroxyl radical. J Clin Invest 1987;80:1486–1491.

    Google Scholar 

  18. Werns, SW, Shea, MJ, Dirscoll, EM, et al. The independent effects of oxygen radical scavengers on canine infarct size. Reduction by superoxide dismutase but not catalase. Circ Res 1985;56:895–898.

    Google Scholar 

  19. Rossen, RD, Swain, JL, Michael, LH, et al. Selective accumulation of the first component of complement and leukocytes in ischemic canine heart muscle. A possible initiator of an extramyocardial mechanism of ischemic injury. Circ Res 1985;57:119–130.

    Google Scholar 

  20. Chatelain, P, Latour, J-G, Tran, D, et al. Neutrophil accumulation in experimental myocardial infarcts: Relation with extent of injury and effect of reperfusion. Circulation 1987;75:1083–1090.

    Google Scholar 

  21. Romson, JL, Hook, BG, Kunkel, SL, et al. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 1983;67:1016–1023.

    Google Scholar 

  22. Mullane, KM, Read, N, Salmon, JA, et al. Role for leukocytes in acute myocardial infarction in anesthetized dogs: Relationship to myocardial salvage by antiinflammatory drugs. J Pharmacol Exp Ther 1984;228:510–552.

    Google Scholar 

  23. Romson, JL, Hook, BG, Rigot, VH, et al. The effect of ibuprofen on accumulation of indium-111-labeled platelets and leukocytes in experimental myocardial infarction. Circulation 1982;66:1002–1011.

    Google Scholar 

  24. Flynn, PF, Becker, WK, Vercellotti, GM, et al. Ibuprofen inhibits granulocyte responses to inflammatory mediators: A proposed mechanism for reduction of experimental myocardial infarct size. Inflammation 1984;8:33–44.

    Google Scholar 

  25. Simpson, PJ, Mitsos, SE, Ventura, A, et al. Prostacyclin protects ischemic-reperfused myocardium in the dog by inhibition of neutrophil activation. Am Heart J 1987;113:129–137.

    Google Scholar 

  26. Simpson, PJ, Mickelson, JK, Fantone, JC, et al. Iloprost inhibits neutrophil function in vitro and in vivo and limits experimental infarct size in canine heart. Circ Res 1987;60:666–673.

    Google Scholar 

  27. Simpson, PJ, Mickelson, J, Fantone, JC, et al. Reduction of experimental canine myocardial infarct size with prostaglandin E1: Inhibition of neutrophil migration and activation. J Pharmacol Exp Ther 1988;244:619–624.

    Google Scholar 

  28. Hill, JH, Ward, PA. C3 leukotactic factors produced by a tissue protease. J. Exp Med 1969;130:505–518.

    Google Scholar 

  29. Hill, JH, Ward, PA. The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med 1971;133:885–900.

    Google Scholar 

  30. Pinckard, RN, Olson, MS, Giclas, PC, et al. Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction. J Clin Invest 1975;56:740–750.

    Google Scholar 

  31. Giclas, PC, Pinckard, RN, Olson, MS. In vitro activation of complement by isolated human heart subcellular membranes. J Immunol 1979;122:146–151.

    Google Scholar 

  32. Storrs, SB, Kolb, WP, Pinckard, RN, et al. Characterization of the binding of purified human Clq to heart mitochondrial membranes. J Biol Chem 1981;256:10924–10929.

    Google Scholar 

  33. Rossen, RD, Michael, LH, Kagiyama, A, et al. Mechanism of complement activation after coronary artery occlusion: Evidence that myocardial ischemia in dogs causes release of constituents of myocardial subcellular origin that complex with human Clq in vivo. Circ Res 1988;62:572–584.

    Google Scholar 

  34. Pinckard, RN, O'Rourke, RA, Crawford, MH, et al. Complement localization and mediation of ischemic injury in baboon myocardium. J Clin Invest 1980;66:1050–1056.

    Google Scholar 

  35. Sasaki, K, Ueno, A, Katori, M, et al. Detection of leukotriene B4 in cardiac tissue and its role in infarct extension through leucocyte migration. Cardiovasc Res 1988;22:142–148.

    Google Scholar 

  36. Bednar, M, Smith, B, Pinto, A, et al. Nafazatrom-induced salvage of ischemic myocardium in anesthetized dogs is mediated through inhibition of neutrophil function. Circ Res 1985;57:131–141.

    Google Scholar 

  37. Shea, MJ, Murtagh, JJ, Jolly, SR, et al. Beneficial effects of nafazatrom on ischemic reperfused myocardium. Eur J Pharmacol 1984;102:63–70.

    Google Scholar 

  38. Anderson, DC, Schamalsteig, FC, Shearer, W, et al. Leukocyte LFA-1, OKM1, p150,95 deficiency syndrome: Functional and biosynthetic studies of three kindreds. Fed Proc 1985;44:2671–2677.

    Google Scholar 

  39. Arnaout, MA, Dana, N, Pitt, J, et al. Deficiency of two human leukocyte surface membrane glycoproteins (Mo1, and LFA-1). Fed Proc 1985;44:2664–2670.

    Google Scholar 

  40. Springer, TA. The LFA-1, Mac-1 glycoprotein family and its deficiency in an inherited disease. Fed Proc 1985;44:2660–2663.

    Google Scholar 

  41. Berger, M, O'Shea, J, Cross, AS. Human neutrophils increase expression of C3bi as well as C3b receptors upon activation. J Clin Invest 1984;74:1566–1571.

    Google Scholar 

  42. Simon, RH, DeHart, PD, Todd, RF. Neutrophil-induced injury of rat pulmonary alveolar epithelial cells. J Cell Invest 1986;78:1375–1386.

    Google Scholar 

  43. Simpson, PJ, Todd, RF, Fantone, JC, et al. Reduction of experimental canine myocardial reperfusion injury by a monoclonal antibody (Anti-Mo-1, Anti-CD11b) that inhibits leukocyte adhesion. J Clin Invest 1988;81:624–629.

    Google Scholar 

  44. Engler, RL, Schmid-Schonbein, GW, Pavelec, RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Pathol 1983;111:98–111.

    Google Scholar 

  45. Hartmann, JR, Robinson, JA, Gunnar, RM. Chemotactic activity in the coronary sinus after experimental myocardial infarction. Effects of pharmacologic interventions on ischemic injury. Am J Cardiol 1977;40:550–555.

    Google Scholar 

  46. Hallett, MB, Shandall, A, Young, HL. Mechanism of protection against “reperfusion injury” by aprotinin: Roles of polymorphonuclear leukocytes and oxygen radicals. Biochem Pharmacol 1985;34:1757–1761.

    Google Scholar 

  47. Bolli, R, Cannon, RO, Speir, E, et al. Role of cellular proteinases in acute myocardial infarction. II. Influence of in vivo suppression of myocardial proteolysis by antipain, leupeptin and pepstatein on myocardial infarct size in the rat. J Am Coll Cardiol 1983;2:681–688.

    Google Scholar 

  48. Ambruso, DR, Johnston, RB. Lactoferrin enhances hydroxyl radical production by human neutrophils, neutrophil particulate fractions, and an enzymatic generating system. J Clin Invest 1981;67:352–360.

    Google Scholar 

  49. Weiss, SJ, Klein, R, Slivka, A, et al. Chlorination of taurine by human neutrophils. J Clin Invest 1982;70:598–607.

    Google Scholar 

  50. Fantone, JC, Ward, PA. Role of oxygen-derived free radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Path 1982;107:397–418.

    Google Scholar 

  51. Jolly, SR, Kane, WJ, Bailie, MB, et al. Canine myocardial reperfusion injury: Its reduction by the combined administration of superoxide dismutase and catalase. Circ Res 1984;54:277–285.

    Google Scholar 

  52. Werns, SW, Simpson, PJ, Mickelson, JK, et al. Sustained limitation by superoxide dismutase of canine myocardial injury due to regional ischemia followed by reperfusion. J Cardiovasc Pharmacol 1988;11:36–44.

    Google Scholar 

  53. Ambrosio, G, Becker, LC, Hutchins, GM, et al. Reduction in experimental infarct size by recombinant human superoxide dismutase: Insights into the pathophysiology of reperfusion injury. Circulation 1986;74:1424–1433.

    Google Scholar 

  54. Richard, VJ, Murry, CE, Jennings, RB, et al. Superoxide dismutase and catalase do not limit infarct size after 90 minutes of ischemia and 4 days of reperfusion in dogs (abstr). Circulation 1987;76:IV-199.

    Google Scholar 

  55. Nejima, J, Canfield, DR, Manders, WT, et al. Failure of superoxide dismutase and catalase to alter size of infarct and functional recovery in conscious dogs with reperfusion (abstr). Circulation 1987;76:IV-198.

    Google Scholar 

  56. Tamura, Y, Driscoll, EM, Senyshyn, JC, et al. Effects of polyethylene glycol-superoxide dismutase on myocardial infarct size and scar formation in the canine heart (abstr). Circulation 1987;76:IV-200.

    Google Scholar 

  57. Simpson, PJ, Mickelson, J, Fantone, JC, et al. Sustained myocardial protection by iloprost with prolonged infusion in a canine model of temporary regional ischemia (abstr). Fed Proc 1987;46:1144.

    Google Scholar 

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

    Google Scholar 

  59. Werns, SW, Shea, MJ, Mitsos, SE. Reduction of the size of infarction by allopurinol in the ischemic-reperfused canine heart. Circulation 1986;73:518–524.

    Google Scholar 

  60. Reimer, KA, Jennings, RB. Failure of the xanthine oxidase inhibitor allopurinol to limit infarct size after ischemia and reperfusion in dogs. Circulation 1985;71:1069–1075.

    Google Scholar 

  61. Werns, SW, Grum, CM, Ventura, A, et al. Effects of allopurinol or oxypurinol on myocardial reperfusion injury (abstr). Circulation 1987;76:IV-97.

    Google Scholar 

  62. Matsuki, T, Shirato, C, Cohen, MV, et al. Oxipurinol and allopurinol reduce infarct size in reperfused dog heart without pretreatment (abstr). Physiologist 1987;30:187.

    Google Scholar 

  63. Puett, DW, Forman, MB, Cates, CU, et al. Oxypurinol limits myocardial stunning but does not reduce infarct size after reperfusion. Circulation 1987;76:678–686.

    Google Scholar 

  64. Kinsman, JM, Murry, CE, Richard, VJ, et al. The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with reperfusion. J Am Coll Cardiol 1988;12:209–217.

    Google Scholar 

  65. Downey, JM, Miura, T, Eddy, LJ, et al. Xanthine oxidase is not a source of free radicals in the ischemic rabbit heart. J Mol Cell Cardiol 1987;19:1053–1060.

    Google Scholar 

  66. Godin, DV, Bhimji, S. Effects of allopurinol on myocardial ischemic injury induced by coronary artery ligation and reperfusion. Biochem Pharmacol 1987;36:2101–2107.

    Google Scholar 

  67. Grum, CM, Ragsdale, RA, Ketai, LH, et al. Absence of xanthine oxidase or xanthine dehydrogenase in the rabbit myocardium. Biochem Biophys Res Com 1986;141:1104–1108.

    Google Scholar 

  68. Grum, CM, Ketai, LH, Myers, CL, et al. Purine efflux after cardiac ischemia: Relevance to allopurinol cardioprotection. Am J Physiol 1987;252:H368-H373.

    Google Scholar 

  69. Das, DK, Engelman, RM, Clement, R, et al. Role of xanthine oxidase inhibitor as free radical scavenger: A novel mechanism of action of allopurinol and oxypurinol in myocardial salvage. Biochem Biophys Res Com 1987;148:314–319.

    Google Scholar 

  70. Myers, CL, Weiss, SJ, Kirsh, MM, et al. Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of globally ischemic and reperfused isolated hearts. J Thorac Cardiovasc Surg 1986; 91:281–289.

    Google Scholar 

  71. Peterson, DA, Kelly, B, Gerrard, JM. Allopurinol can act as an electron transfer agent. Is this relevant during reperfusion injury? Biochem Biophys Res Com 1986;137:76–79.

    Google Scholar 

  72. Moorhouse, PC, Grootveld, M, Halliwell, B, et al. Allopurinol and oxypurinol are hydroxyl radical scavengers. FEBS Lett 1987;213:23–28.

    Google Scholar 

  73. Hoey, BM, Butler, J, Halliwell, B. On the specificity of allopurinol and oxypurinol as inhibitors of xanthine oxidase. A pulse radiolysis determination of rate constants for reaction of allopurinol and oxypurinol with hydroxyl radicals. Free Rad Res Comms 1988;4:259–263.

    Google Scholar 

  74. Zimmerman, BJ, Parks, DA, Grisham, MB, et al. Allopurinol does not enhance antitoxidant properties of extracellular fluid. Am J Physiol 1988;255H202-H206.

    Google Scholar 

  75. Watts, RWE, Watts, JEM, Seegmiller, JE. Xanthine oxidase activity in human tissues and its inhibition by allopurinol. J Lab Clin Med 1965;66:688–697.

    Google Scholar 

  76. Eddy, LJ, Stewart, JR, Jones, HP, et al. The free radical producing enzyme, xanthine oxidase, is undetectable in human hearts. Am J Physiol 1987;253:H709-H711.

    Google Scholar 

  77. Jarasch, E-D, Bruder, G, Heid, HW. Significance of xanthine oxidase in capillary endothelial cells. Acta Physiol Scand 1986;548:39–46.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine(Division of Cardiology), The University of Michigan Medical School, 48109, Ann Arbor, Michigan

    Steven W. Werns

  2. Department of Pharmacology, The University of Michigan Medical School, 48109, Ann Arbor, Michigan

    Benedict R. Lucchesi

Authors
  1. Steven W. Werns
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benedict R. Lucchesi
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This study was supported by the National Institutes of Health, Heart, Lung and Blood Institute, Grant #19782-06 and by a Grant-in-Aid from the American Heart Association of Michigan. Dr. Werns is the recipient of a Physician Scientist Award from the National Institutes of Health, Heart, Lung and Blood Institute, Grant #HL-01409-01.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Werns, S.W., Lucchesi, B.R. Myocardial ischemia and reperfusion: The role of oxygen radicals in tissue injury. Cardiovasc Drug Ther 2, 761–769 (1989). https://doi.org/10.1007/BF00133206

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00133206

Key Words

Search

Navigation