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Cardiovascular Drugs and Therapy

, Volume 10, Issue 3, pp 331–339 | Cite as

EUK-8 a synthetic catalytic scavenger of reactive oxygen species protects isolated iron-overloaded rat heart from functional and structural damage induced by ischemia/reperfusion

  • S. Pucheu
  • F. Boucher
  • T. Sulpice
  • N. Tresallet
  • Y. Bonhomme
  • B. Malfroy
  • J. de Leiris
Ischemia and Reperfusion

Summary

The effects of EUK-8, a synthetic, catalytic scavenger of reactive oxygen species, on isolated iron-overloaded rat hearts submitted to ischemia-reperfusion were studied. In the absence of EUK-8, functional parameters (systolic and diastolic pressures, oxygen consumption as estimated by the product heart rate times left ventricular diastolic pressure) were severely impaired 1 minute and 15 minutes after reperfusion following a 15 minute ischemic episode. Dimethylthiourea (10 mM), a hydroxyl radical scavenger, had a minimally protective effect. In contrast, EUK-8 at a concentration of 50 μM in the perfusion medium maintained these parameters at close to their preischemia values. Electron microscopic analysis of heart tissues after 15 minutes ischemia followed by 15 minutes reperfusion showed extensive damage to mitochondria and sarcomeres in untreated hearts, while the extent of damage was significantly lower in EUK-8-treated hearts. The functional and structural protection afforded by EUK-8 were significantly better than those induced by dimethylthiourea. These data suggest that EUK-8 may be therapeutically useful in preventing heart damage induced by ischemia-reperfusion, for example, during thrombolytic treatment of myocardial infarction.

Key Words

ischemia-reperfusion oxygen free radicals isolated rat heart iron overload EUK-8 

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References

  1. 1.
    BraunwaldE, KlonerRA. The stunned myocardium: Prolonged postischemic ventricular dysfunction.Circulation 1982;66:1146–1149.PubMedGoogle Scholar
  2. 2.
    BernierM, ManningAS, HearseDJ. Reperfusion arrhythmias: Dose-related protection by anti free radical interventions.Am J Physiol 1989;256:1344–1352.Google Scholar
  3. 3.
    BolliR. Oxygen-derived free radicals and myocardial reperfusion injury: An overview.Cardiovasc Drugs Ther 1991;5: 249–268.PubMedCrossRefGoogle Scholar
  4. 4.
    OpieLH. Reperfusion injury and its pharmacologic modification.Circulation 1989;80:1049–1062.PubMedGoogle Scholar
  5. 5.
    McCordJM. Oxygen-derived free radicals in post-ischemic tissue injury.N Engl J Med 1985;312:159–163.PubMedCrossRefGoogle Scholar
  6. 6.
    ManningAS. Reperfusion induced arrhythmias: Do free radicals play a critical role?Free Radic Biol Med 1988;4: 305–316.PubMedCrossRefGoogle Scholar
  7. 7.
    YamadaM, HearseDJ, CurtisMJ. Reperfusion and readmission of oxygen. Pathophysiological relevance to oxygenderived free radical to arrhythmogenesis.Cir Res 1990;67: 1211–1224.Google Scholar
  8. 8.
    HalliwellB. Superoxide, iron, vascular endothelium and reperfusion injury.Free Radic Res Commun 1989;5:315–318.PubMedGoogle Scholar
  9. 9.
    ZweierJL. Measurement of superoxide-derived free radicals in the reperfused heart: Evidence for a free radical mechanism of reperfusion injury.J Biol Chem 1988;263: 1353–1357.PubMedGoogle Scholar
  10. 10.
    ArroyoCM, KramerJH, DickensBF, WeglickiWB. Identification of free radicals in myocardial ischemia/reperfusion by spin-trapping with nitrone DMPO.FEBS Lett 1987;221: 101–1047.PubMedCrossRefGoogle Scholar
  11. 11.
    ZweierJL, FlahertyJT, WeisfeldtML. Direct measurement of free radical generation following reperfusion of ischemic myocardium.Proc Natl Acad Sci USA 1987;84: 1404–1407.PubMedCrossRefGoogle Scholar
  12. 12.
    AmbrosioG, FlahertyJT, DuilioC, et al. Oxygen radicals generated at reflow induce peroxidation of membrane lipids in reperfused hearts.J Clin Invest 1991;87:2056–2066.PubMedGoogle Scholar
  13. 13.
    FarberNE, VercellottiGM, JacobHS, PieperGM, GrossGJ. Evidence for a role of iron-catalysed oxidants in functional and metabolic stunning in the canine heart.Circ Res 1988;63:351–360.PubMedGoogle Scholar
  14. 14.
    OzakiM, KawabataT, AwaiM. Iron release from haemosiderin and production of iron-catalysed hydroxyl radicals in vitro.Biochem J 1988;250:589–595.PubMedGoogle Scholar
  15. 15.
    PucheuS, CoudrayC, TresalletN, FavierA, deLeirisJ. Effect of iron overload in the isolated ischemic and reperfused rat heart.Cardiovasc Drugs Ther 1993;7:701–711.PubMedCrossRefGoogle Scholar
  16. 16.
    PrzylenkK, KlonerRA. Superoxide dismutase plus catalase improve contractile function in the canine model of the “stunned myocardium.”Circ Res 1986;58:148–156.Google Scholar
  17. 17.
    BolliR. Superoxide dismutase 10 years later: A drug in search of use.J Am Coll Cardiol 1991;18:231–233.PubMedCrossRefGoogle Scholar
  18. 18.
    BaudryM, EtienneS, BruceA, PaluckiM, JacobsenE, MalfroyB. Salen-manganese complexes are superoxide dismutase mimics.Biochem Biophys Res Commun 1993;192: 964–968.PubMedCrossRefGoogle Scholar
  19. 19.
    Gonzalez PK, Doctrow SR, Fink MP. EUK-8, an SOD/cat mimic, protects against lactic acidosis-induced hyperpermeability and lipid peroxidation in Caco-2BBE monolayers.FASEB J 1995;A953.Google Scholar
  20. 20.
    Malfroy-Camine B, Baudry, M. Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease. U.S. patent number 5,403,934, 1995.Google Scholar
  21. 21.
    GonzalezPK, ZhuangJ, DoctrowSR, MalfroyB, BensonPF, MenconiMJ, FinkMP. EUK-8, a synthetic SOD and catalase mimetic, ameliorates acute lung injury in endotoxemic swine.J Pharmacol Exp Therape 1995;275:798–806.Google Scholar
  22. 22.
    MuslehW, BruceA, MalfroyB, BaudryM. Effects of EUK-8, a synthetic catalytic superoxide scavenger, on hypoxia-and acidosis-induced damage in hippocampal slices.Neuropharmacology 1994;33:929–934.PubMedCrossRefGoogle Scholar
  23. 23.
    BoucherF, PucheuS, CoudrayC, FavierA, deLeirisJ. Evidence of cytosolic iron release during post-ischaemic reperfusion of isolated rat hearts: Influence on spin-trapping experiments with DMPO.FEBS Lett 1992;302:261–264.PubMedCrossRefGoogle Scholar
  24. 24.
    KrebsHA, HenseleitK. Untersuchungen über die Harnstoffbildung im Tierköper.Hoppe Seyler's Z 1932;210: 33–66.Google Scholar
  25. 25.
    LangendorffO. Untersuchungen am überlebenden Säugetierherzen.Pflügers Arch 1895;61:291–332.CrossRefGoogle Scholar
  26. 26.
    CurtisMJ, McLeodBA, TabritzchiR. An improved perfusion apparatus for small animal hearts.J Pharmacol Methods 1986;15:87–94.PubMedCrossRefGoogle Scholar
  27. 27.
    FeurrayD, deLeirisJ. Ultrastructural modifications induced by reoxygenation in the anoxic isolated rat heart perfused without exogenous substrate.J Mol Cell Cardiol 1975;7:307–314.CrossRefGoogle Scholar
  28. 28.
    SchaperJ, MeiserE, StammlerG. Ultrastructural morphometric analysis of myocardium from dogs, rats, hamsters, mice and from human hearts.Circ Res 1985;56:377–391.PubMedGoogle Scholar
  29. 29.
    SnedecorGW, CochranWG.Statistical Methods. Ames, IA: The Iowa State University Press, 1967.Google Scholar
  30. 30.
    ZimmermanJJ. Therapeutic applications of oxygen radical scavengers.Chest 1991;110:1895–1925.Google Scholar
  31. 31.
    HearseDJ, TosakiA. Reperfusion-induced arrhythmias and free radicals: studies in the rat heart with DMPO.J Cardiovasc Pharmacol 1987;9:641–650.PubMedCrossRefGoogle Scholar
  32. 32.
    NeelyJR, MorganHE. Relationship between carbohydrate and lipid metabolism and energy balance of heart muscle.Ann Rev Physiol 1974;36:413–459.CrossRefGoogle Scholar
  33. 33.
    GauduelY, DuvelleroyMA. Role of oxygen radicals in cardiac injury due to reoxygenation.J Mol Cell Cardiol 1984; 16:459–470.PubMedCrossRefGoogle Scholar
  34. 34.
    KlonerRA, PrzyklenkK, WhittakerP. Deleterious effects of oxygen radicals in ischemia/reperfusion. Resolved and unresolved issues.Circulation 1989;80:1115–1127.PubMedGoogle Scholar
  35. 35.
    Karwatowska-ProkopczukE, CzarnowskaE, BeresewiezA. Iron availability and free radical induced injury in the isolated ischaemic/reperfused rat heart.Cardiol Res 1992; 26:58–66.CrossRefGoogle Scholar
  36. 36.
    Van derHeideRS, SobotkaPA, GanoteCE. Effect of the free radical scavenger DMTU and mannitol on the oxygen paradox in perfused rat hearts.J Mol Cell Cardiol 1987;19: 615–625.CrossRefGoogle Scholar
  37. 37.
    BolliR, PatelBS, ZhuWX, O'NeillPG, HartleyCJ, CharlatML. The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction.Am J Physiol 1987;253: 1372–1380.Google Scholar
  38. 38.
    MyersCL, WeissSJ, KirshMM, ShepardBM, ShlaferM. Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of global ischemic and reperfused isolated hearts.J Thor Cardiovasc Surg 1986;91:281–289.Google Scholar
  39. 39.
    FoxRB. Prevention of granulocyte-mediated oxidant lung injury in rats by a hydroxyl radical scavenger, dimethylthiourea.J Clin Invest. 1984;74:1456–1464.PubMedCrossRefGoogle Scholar
  40. 40.
    HalliwellB, GutteridgeJMC.Free Radicals in Biology and Medicine. New York: Oxford University Press, 1989.Google Scholar
  41. 41.
    HalliwellB, GutteridgeJMC. Oxygen toxicity, oxygen radicals, transition metals and disease.Biochem. J. 1984;219: 1–14.PubMedGoogle Scholar
  42. 42.
    ZimmermanANE. Therapeutic applications of oxygen radical scavengers.Chest 1991;110:1895–1925.Google Scholar
  43. 43.
    BruceA, MuslehW, MalfroyB, BaudryM. Effects of salen manganese complex, a SOD-mimic, in various models of neuronal pathology (abstr).Abstr Soc Neurosci Meeting 1993; 19:1680.Google Scholar
  44. 44.
    AmbrosioG, FlahertyJT. Effects of the superoxide radical scavenger superoxide dismutase, and ff the hydroxyl radical scavenger mannitol, on reperfusion injury in isolated rabbit hearts.Cardiovasc Drugs Ther 1992;6:623–632.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 1996

Authors and Affiliations

  • S. Pucheu
    • 1
  • F. Boucher
    • 1
  • T. Sulpice
    • 1
  • N. Tresallet
    • 1
  • Y. Bonhomme
    • 2
  • B. Malfroy
    • 3
  • J. de Leiris
    • 1
  1. 1.Groupe de Physiopathologie Cellulaire Cardiaque, URA CNRS 1287Université Joseph FourierGrenobleFrance
  2. 2.Lipha, s.a.LyonFrance
  3. 3.EukarionBedfordUSA

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