Skip to main content
SpringerLink
Log in

Intracoronary infusion of superoxide dismutase and reperfusion injury in the pig heart

  • Original Contributions
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Summary

The effects of an intracoronary infusion of superoxide dismutase on infarct size were studied in 16 pigs submitted to a 48-min coronary occlusion of the mid left anterior descending coronary artery followed by reperfusion for 24 h. Areas at risk marked with fluoresccine and infarct sizes calculated with triphenyl tetrazolium chloride staining 24 h after the occlusion were similar in the five control animals with coronary reperfusion alone, in the five animals with an intracoronary infusion of lactate Ringer initiated 3 min before reperfusion and maintained for 33 min and in the six animals with superoxide dismutase added to the solution of lactate Ringer and infused at a rate of 2500 units/min. The ratios infarct size/area at risk were respectively 0.50±0.10, 0.63±0.10 and 0.65±0.04 in the three study groups (NS). The extent of intramyocardial hemorrhage, evaluated by morphometric analysis was also similar 0.90±0.29×106, 0.70±0.14 and 1.62±0.42 red blood cells/mm3 of tissue (NS). The superoxide dismutase infusion, however, resulted in significantly fewer early reperfusion arrhythmias which involved 23±15 s of each minute electrocardiographic recording in the superoxide dismutase group, compared to 37±13 s in the lactate Ringer group and 45±14 s in the control group (p=0.004). The lack of an effect of intracoronary infusion of superoxide dismutase on infarct size suggests that in this experimental model, extracellular superoxide radicals generated during early reperfusion have no major role on myocardial cell necrosis and microvascular damage. Reperfusion arrhythmias were, however, reduced.

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. Ambrosio G, Becker LC, Hutchins GM, Weisman HE, Weisfeldt ML (1986) Reduction in experimental infarct size by recombinant human superoxide dismutase: insights into the pathophysiology of reperfusion injury. Circulation 74:1424–1433

    PubMed  Google Scholar 

  2. Ambrosio G, Zweier JL, Jacobus WE, Weisfeldt ML, Flaherty JT (1987) Improvement of postischemic myocardial function and metabolism induced by administration of deferoxamine at the time of reflow: the role of iron in the pathogenesis of reperfusion injury. Circulation 76:906–915

    PubMed  Google Scholar 

  3. Bernier M, Hearse DJ, Manning AS (1986) Reperfusion-induced arrhythmias and oxygen-derived free radicals. Studies with “anti-free radical” interventions and a free radical generating system in the isolated perfused rat heart. Circ Res 58:331–340

    PubMed  Google Scholar 

  4. Bolli R, Zhu W, Hartley CJ, Michael LH, Repine JE, Hess ML, Kukreja RC, Roberts R (1987) Attenuation of dysfunction in the postischemic “stunned” moycardium by dimethylthiourea. Circulation 76:458–468

    PubMed  Google Scholar 

  5. Das DK, Engelman RM, Rouson JA, Breyer RH, Otani H, Lemeshow S (1986) Pathophysiology of superoxide radical as potential mediator of reperfusion injury in pig heart. Basic Res Cardiol 81:155–166

    PubMed  Google Scholar 

  6. de Lorgeril M, Rousseau G, Basmadjian A, Latour JG (1988) Lignocaine in experimental myocardial infarction: failure to prevent neutrophil accumulation and ventricular fibrillation and to reduce infarct size. Cardiovasc Res 22:439–446

    PubMed  Google Scholar 

  7. Eddy LJ, Stewart JR, Jones HP, Engerson TD, McCord JM, Downey JM (1987) Free radical producing enzyme, xanthine oxidase, is undetectable in human hearts. Am J Physiol 253:H709-H711

    PubMed  Google Scholar 

  8. Engler R, Covell JW (1987) Granulocytes cause reperfusion ventricular dysfunction after 15-minute ischemia in the dog. Circ Res 61:20–28

    PubMed  Google Scholar 

  9. Engler R, Gilpin E (1989) Can superoxide dismutase alter myocardial infarct size? Circulation 79:1137–1142

    PubMed  Google Scholar 

  10. Forman MB, Puett DW, Cates CU, McCroskey DE, Beckman JK, Greene HL, Virmani R (1988) Glutathione redox pathway and reperfusion injury. Effect of N-Acetylcysteine on infarct size and ventricular function. Circulation 78:202–213

    PubMed  Google Scholar 

  11. Fujiwara H, Ashraf M, Sato S, Millard RW (1982) Transmural cellular damage and blood flow distribution in early ischemia in pig hearts. Circ Res 51:683–693

    PubMed  Google Scholar 

  12. Fuster V, Frye RL, Kennedy MA, Connoly DC, Mankin HT (1979) The role of collateral circulation in the various coronary syndromes. Circulation 59:1137–1144

    PubMed  Google Scholar 

  13. Gallagher KP, Buda AJ, Pace D, Gerren RA, Shlafer M (1986) Failure of superoxide dismutase and catalase to alter size of infarction in conscious dogs after 3 hours of occlusion followed by reperfusion. Circulation 73:1065–1076

    PubMed  Google Scholar 

  14. Garcia-Dorado D, Théroux P, Desco M, Solares J, Elizaga J, Fernandez-Avilés F, Alonso J, Soriano J (1989) Cell-to-cell interaction: a mechanism to explain the wavefront progression of myocardial necrosis. Am J Physiol 256:H1266–1273

    PubMed  Google Scholar 

  15. Garcia-Dorado D, Théroux P, Elizaga J, Fernandez-Avilés F, Alonso J, Solares J (1988) Influence of tachycardia and arterial hypertension on infarct size in the pig. Cardiovasc Res 22: 620–626

    PubMed  Google Scholar 

  16. Garcia-Dorado D, Théroux P, Elizaga J, Galinanes M, Solares J, Riesgo M, Gomez MJ, Garcia-Dorado A, Fernandez-Avilés F (1987) Myocardial reperfusion in the pig heart model: infarct size and duration of coronary occlusion. Cardiovasc Res 21:537–544

    PubMed  Google Scholar 

  17. Garcia-Dorado D, Théroux P, Fernandez-Avilés F, Elizaga J, Solares J, Galinanes M (1987) Diltiazem and progression of myocardial ischemic damage during coronary artery occlusion and reperfusion in porcine hearts. J Am Coll Cardiol 10:906–911

    PubMed  Google Scholar 

  18. Garcia-Dorado D, Théroux P, Solares J, Alonso J, Fernandez-Avilés F, Elizaga J, Soriano J, Botas J, Munoz R (1990) Determinants of hemorrhagic infarcts. Histologic observations from experiments involving coronary occlusion, coronary reperfusion and reocclusion. Am J Pathol 137:301–311

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  20. Hattori N, Drury JK, Satomura K, Miyazaki A, Corday E (1987) Reduction of infarct size with retrograde but not antegrade administration of superoxide dismutase in pigs (abstr). Circulation 76 (Suppl IV):200

    Google Scholar 

  21. Jully SR, Kane WJ, Bailie MB, Abrams GD, Lucchesi BR (1984) Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circ Res 54:277–285

    PubMed  Google Scholar 

  22. Karagucuzian HS, Mandel WJ (1987) Electrophysiologic mechanisms of ischemic ventricular arrhythmias. In: Mandel WJ (ed) Cardiac arrhythmias, their mechanisms, diagnosis and management. Lippincott JB Co., Philadelphia, pp 452–474

    Google Scholar 

  23. Kim M, Akera T (1987) O2 free radicals: cause of ischemia reperfusion injury to cardiac Na+−K+-ATPase. Am J Physiol 252:H252-H257

    PubMed  Google Scholar 

  24. Kinsman III JM, Murry CE, Richard VJ, Jennings RB, Reimer KA (1988) The xanthine oxidase inhibitor oxypurinol does not limit infarct size in a canine model of 40 minutes of ischemia with superfusion. J Am Coll Cardiol 12:209–217

    PubMed  Google Scholar 

  25. Kusuma Y, Bernier M, Hearse DJ (1989) Singlet oxygen-induced arrhythmias. Circulation 80:1430–1448

    Google Scholar 

  26. Limm WM, Mugilishi MM, Schwartz SM, McNamara J (1988) Oxygen free radical scavengers do not reduce infarct size in baboons (abstr). J Am Coll Cardiol 11:163A

    Google Scholar 

  27. Luber JM, Rujikarn N, Rao PS (1987) Generation of free radicals during myocardial ischemia and reperfusion time course and identity (abstr). Circulation 76 (Suppl IV):199

    Google Scholar 

  28. McCord JM (1984) Are free radicals a major culprit? In: Hearse DJ, Yellow DM (eds) Therapcutic approaches to myocardial infarct size limitation. Raven Press, New York, pp 209–218

    Google Scholar 

  29. McDonagh PF, Reynolds JM (1987) Transcoronary exchange during reperfusion after myocardial ischemia. In: McDonagh PF (ed) microvascular perfusion and transport in health and disease. Skarger Publisher, Basel, pp 169–203

    Google Scholar 

  30. Mitsos SE, Askew TE, Fantone JC, Kunel SL, Abrams GD, Schork A, Lucchesi BR (1986) Protective effects of N-2-mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in the dog: evidence for the role of intracellular-derived free radicals. Circulation 73:1077–1086

    PubMed  Google Scholar 

  31. Muxfeldt M, Schaper W (1987) The activity of xanthine oxidasenin in heart of pigs, guinca pigs, rabbits, rats and humans. Basic Res Cardiol 82:486–492

    PubMed  Google Scholar 

  32. Myers ML, Bolli R, Lekich RF, Hartley CJ, Roberts R (1985) Enhancement of recovery of myocardial function by oxygen free-radical scavengers after reversible regional ischemia. Circulation 72:915–921

    PubMed  Google Scholar 

  33. Naslund U, Marklund S, Reiz S (1988) Superoxide dismutase limits myocardial infarct size in a porcine closed chest ischemia-reperfusion model (abstr). J Am Coll Cardiol 11:163A

    Google Scholar 

  34. Nejima J, Knight DR, Fallon JT, Uemura N, Manders WT, Canfield DR, Cohen MV, Vatner SF (1989) Superoxide dismutase reduces reperfusion arrhythmias but fails to salvage regional function or myocardium at risk in conscious dogs. Circulation 79:143–153

    PubMed  Google Scholar 

  35. Pallandi RT, Perry MA, Campbell TJ (1987) Proarrhythmic effects of an oxygen-derived free radicals generating system on action potentials recorded from guinea pig ventricular myocardium: A possible cause of reperfusion induced arrhythmias. Circ Res 61:50–54

    PubMed  Google Scholar 

  36. Peck SL, Johnston RB Jr, Horowitz LD (1985) Reduced neutrophil superoxide anion release after prolonged infusions of lidocaine. J Pharmacol Exp Ther 235:418–422

    PubMed  Google Scholar 

  37. Przyklenk K, Kloner RA (1986) Superoxide dismutase plus catalase improve contractile function in the canine model of the “stunned myocardium”. Circ Res 58:148–156

    PubMed  Google Scholar 

  38. Przyklenk K, Kloner RA (1989) “Reperfusion Injury” by oxygen-derived free radicals? Effect of superoxide dismutase plus catalase, given at the time of reperfusion, on myocardial infarct size, contractile function, coronary microvasculature, and regional myocardial blood flow. Circ Res 64:86–96

    PubMed  Google Scholar 

  39. Puett DW, Forman MB, Cates CU, Wilson BH, Hande KR, Friesinger GC, Virmani R (1987) Oxypurinol limits myocardial stunning but does not reduce infarct size after reperfusion. Circulation 76:678–686

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  41. Richard VJ, Murry CE, Jennings RB, Reimer KA (1988) Therapy to reduce free radicals during early reperfusion does not limit the size of myocardial infarcts caused by 90 minutes of ischemia in dogs. Circulation 78:473–480

    PubMed  Google Scholar 

  42. Schaper W, Binz K, Sass S, Winkler B (1987) Influence of collateral blood flow and of variations in MVO2 on tissue—ATP content in ischemic and infarcted myocardium. J Moll Cell Cardiol 19:19–25

    Google Scholar 

  43. Simpson PJ, Fantone JC, Mickleson JK, Gallagher KP, Lucchesi BR (1988) Identification of a time window for therapy to reduce experimental canine myocardial injury: suppression of neutrophil activation during 72 hours of reperfusion. Circ Res 63:1070–1079

    PubMed  Google Scholar 

  44. Snyder DW, Crafford WA, Glashow JL, Rankin D, Sobel BE, Corr PB (1981) Lysophosphoglycerides in ischemic myocardium effluents and potentiation of their arrhythmogenic effects. Am J Physiol 241:H700-H707

    PubMed  Google Scholar 

  45. Tamura Y, Chi L, Driscoll EM, Hoff PT, Freeman BA, Gallagher KP, Lucchesi BR (1988) Superoxide dismutase conjugated to polyethylene glycol provides sustained protection against myocardial ischemia/reperfusion injury. Circ Res 63:944–959

    PubMed  Google Scholar 

  46. Thompson JA, Hess ML (1986) The oxygen free radical system: a fundamental mechanism in the production of myocardial necrosis. Prog Cardiovasc Dis 28:449–462

    PubMed  Google Scholar 

  47. Tranum-Jansen J, Janse MJ, Fiolet JWT, Krieger WJG, Neumann d'Alnoncourt C, Durrer D (1981) Tissue osmolality, cell swelling and reperfusion in acute regional myocardial ischemia in the isolated porcine heart. Circ Res 49:364–387

    PubMed  Google Scholar 

  48. Uraizee A, Reimer KA, Murry CE, Jennings RB (1987) Failure of superoxide dismutase to limit size of myocardial infarction after 40 minutes of ischemia and 4 days of reperfusion in dogs. Circulation 75:1237–1248

    PubMed  Google Scholar 

  49. Werns SW, Grum CM, Ventura A, Lucchesi BR (1987) Effect of allopurinol or oxipurinol on myocardial reperfusion injury (abstr). Circulation 76 (Suppl IV):197

    Google Scholar 

  50. Werns SW, Shea MJ, Driscoll EM, Cohen C, Abrams GD, Pitt B, Lucchesi BR (1985) The independent effects of oxygen radical scavengers on canine infarct size. Reduction by superoxide dismutase but not catalase. Circ Res 56:895–898

    PubMed  Google Scholar 

  51. Werns SW, Shea MJ, Mitsos SE, Dysko RC, Fantone JC, Schork MA, Abrams GD, Pitt B, Lucchesi BR (1986) Reduction of the sizc of infarction by allopurinol in the ischemic-reperfused canine heart. Circulation 73:518–524

    PubMed  Google Scholar 

  52. Zweier J (1988) Measurement of superoxide-derived free radicals in the reperfused heart. Evidence for a free radical mechanism of reperfusion injury. J Biol Chem 263:1353–1357

    PubMed  Google Scholar 

Download references

Author information

Author notes

  1. D. Garcia-Dorado

    Present address: Servicio de Cardiología y Departmento de Medicina Experimental, Hospital General Gregorio Maranon, Doctor Esquerdo, 46, 28007, Madrid, Spain

Authors and Affiliations

  1. Servicio de Cardiología y Departmento de Medicina Experimental, Hospital General Gregorio Maranon, Doctor Esquerdo, 46, 28007, Madrid, Spain

    J. Alonso, J. Elizaga, J. Botas, F. Fernandez-Avilés, J. Soriano, R. Munoz & J. Solares

  2. Montreal Heart Institute, Montreal, Quebec, Canada

    P. Théroux

Authors
  1. D. Garcia-Dorado
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. Théroux
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Alonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Elizaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Botas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F. Fernandez-Avilés
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Soriano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Munoz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Solares
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Partially supported by a grant PA 86/0389 from the Comisión Interministerial de Ciencia y Tecnología (CICYT), grant 1/86 from the Sección de Cardiopatía isquemica de la Sociedad Española de Cardiología and grant 17/88 of the Convenio Madrid-Quebec.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Garcia-Dorado, D., Théroux, P., Alonso, J. et al. Intracoronary infusion of superoxide dismutase and reperfusion injury in the pig heart. Basic Res Cardiol 85, 619–629 (1990). https://doi.org/10.1007/BF01907896

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01907896

Key words

Search

Navigation