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Basic Research in Cardiology

, Volume 85, Issue 1, pp 55–70 | Cite as

Role of a nonsteroidal anti-inflammatory agent, ibuprofen, in coronary revascularization after acute myocardial infarction

  • R. Clement
  • D. K. Das
  • R. M. Engelman
  • H. Otani
  • D. Bandhyopadhyay
  • S. Hoory
  • M. Antar
  • J. A. Rousou
  • R. H. Breyer
  • M. R. Prasad
Original Contributions

Summary

The efficacy of using a nonsteroidal anti-inflammatory agent such as ibuprofen for the salvage of ischemic and reperfused myocardium was investigated by examining its ability to improve global and regional functions as well as to preserve high-energy phosphate compounds and inhibit creatine kinase release from an isolated in-situ pig heart subjected to 1 h of normothermic regional ischemia followed by 1 h of global hypothermic arrest and 1 h of normothermic reperfusion. Preperfusion of the heart for 15 min prior to ischemic insult with 50 μM ibuprofen failed to mitigate the myocardial reperfusion injury. Ibuprofen, however, functioned as an anti-inflammatory agent, as judged by its ability to inhibit the influx of indium-111-labeled polymorphonuclear leukocytes and chromium-51 (51Cr)-labeled platelets into the ischemic and reperfused heart. It also blocked the cyclooxygenase pathway, as evidenced by the significant reduction of 6-keto-prostaglandin F and thromboxane B2 concentrations in the perfusate. Inhibition of cyclooxygenase resulted in increased accumulation of nonesterified fatty acids, particularly arachidonic acid, in the heart. These results suggest that although ibuprofen can inhibit polymorphonuclear leukocyte and platelet influx into the ischemic and reperfused heart, it causes further damage to the already ischemic heart by reducing prostacyclin concentration and increasing free fatty acids in the heart.

Key words

ischemia reperfusioninjury ibuprofen prostaglandins neutrophils 

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References

  1. 1.
    Aas KA, Gardner FH (1958) Survival of blood platelets labeled with chromium. J Clin Invest 37:1257–1268PubMedGoogle Scholar
  2. 2.
    Bandyopadhyay D, Schiff RG, Hoory S, Moskowitz GW, Levy LM, Das DK (1987)111Indiumtropolone labeled human PMNs: a rapid method of preparation and evaluation of labeling parameters. Inflammation 11:13–22PubMedGoogle Scholar
  3. 3.
    Bednar M, Smith B, Mullane K (1984) Nafazatrom-induced inhibition of neutrophil function mediates salvage of ischemia myocardium. Fed Proc 43:389Google Scholar
  4. 4.
    Bednar M, Smith B, Pinto A, Mullane KM (1985) Neutrophil depletion suppresses111In-labeled platelet accumulation in infarcted myocardium. J Cardiovasc Pharmacol 7:906–912PubMedGoogle Scholar
  5. 5.
    Bertolatus JA, Ridolfi RL, Hutchins GM (1974) Complete heart block caused by calcific mitral annulus fibrosus. Johns Hopkins Med J 135:199–203PubMedGoogle Scholar
  6. 6.
    Bittl JA, Pfeffer MA, Lewis RA, Mehrotra MM, Corey EJ, Austen FK (1985) Mechanism of the negative inotropic action of leukotriencs C4 and D4 on isolated rat heart. Cardiovasc Res 19:426–432PubMedGoogle Scholar
  7. 7.
    Bonow RO, Lipson LS, Sheehan FH, Capurro NL, Isner JM, Roberts WC, Goldstein RE, Epstein SE (1981) Lack of effect of aspirin on myocardial infarct size in dog Am J Cardiol 47:258–264PubMedGoogle Scholar
  8. 8.
    Chatelain P, Latour JG, Tran D, Lorgeril MD, Dupras G, Bourass M (1987) Myocardial infarcts: relation with extent of injury and effect of reperfusion. Circulation 75:1083–1090PubMedGoogle Scholar
  9. 9.
    Chesbro JH, Fuster V, Elveback LR, Clements IP, Smith HC, Holmes DR, Bardsley WT, Pluth JR, Wallace RB, Puga FJ, Orzsulak TA, Piehler JM, Danielson GK, Schaff HV, Frye RL (1984) Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med 310:209–214PubMedGoogle Scholar
  10. 10.
    Chien KR, Han A, Sen A, Buja LM, Willerson JT (1984) Accumulation of unesterified arachidonic acid in ischemic canine myocardium. Circ Res 54:313–322PubMedGoogle Scholar
  11. 11.
    Cordis G, Engelman RM, Das DK (1987) Simultaneous qualification of myocardial adenine nucleotides and creatine phosphate by ion-pair reversed-phase high performance liquid chromatography. J Chromatogr 386:283–288PubMedGoogle Scholar
  12. 12.
    Cordis GA, Prasad MR, Otani H, Engelman RM, Das DK (1987) Measurement of polyunsaturated fatty acids and acyl chain composition of myocardial lipids by high performance liquid chromatography. Chromatographia (in press)Google Scholar
  13. 13.
    Curnulle JT (1984) Studies on the mechanism of superoxide release from human neutrophils stimulated with arachidonate. J Biol Chem 259:11851–11857PubMedGoogle Scholar
  14. 14.
    Das DK (1986) Modulation of deacylation-reacylation pathway of phospholipid metabolism and turnover during reperfusion of ischemic myocardium. In: Freyez L, Dreyfus H, Massarelli R, Gatt S (eds) Enzymes of lipid metabolism II; Plenum Publishing Corp, New York, pp 93–98Google Scholar
  15. 15.
    Das DK, Engelman RM, Flansaas D, Otani H, Rousou J, Breyer RH (1987) Development-profiles of protective mechanisms of heart against peroxidative injury. Basic Res Cardiol 82:36–50PubMedGoogle Scholar
  16. 16.
    Das DK, Engelman RM, Rousou JA, Breyer RH, Otani H, Lemeshow, S (1986) Pathophysiology of superoxide radical as potential mediator of reperfusion injury in pig heart. Basic Res Cardiol 81:155–166PubMedGoogle Scholar
  17. 17.
    Das DK, Engelman RM, Rousou JA, Breyer RH, Otani H, Lemeshow S (1986) Role of membrane phospholipids in myocardial injury induced by ischemia and reperfusion. Am J Physiol 251:H71-H79PubMedGoogle Scholar
  18. 18.
    Engler R, Schmid-Schonbein GW, Paveler LR (1981) Role of leukocyte-capillary plugging in preventing myocardial reperfusion. Circulation 64 (suppl IV):138Google Scholar
  19. 19.
    Ezra D, Boyd LM, Feuerstein G, Goldstein RE (1983) Coronary constriction by leukotriene C4, D4, and E4 in the intact pig heart. Am J Cardiol 51:1451–1454PubMedGoogle Scholar
  20. 20.
    Fantone J, Ward P (1982) Role of oxygen-derived free radical and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol 107:397–418Google Scholar
  21. 21.
    Feuvray D, Leiris J (1975) Ultrastructural modifications induced by reoxygenation in the anoxic isolated rat heart perfused without exogenous substrate. J Mol Cell Cardiol 7:307–314PubMedGoogle Scholar
  22. 22.
    Fiedler VB, Abram TS (1987) Effects of intracoronary leukotriene D4 infusion on the coronary circulation, hemodynamics, and prostanoid release in porcine experiments. Cardiology 74:89–99PubMedGoogle Scholar
  23. 23.
    Hearse DJ, Humphrey WG, Nayler WG, Slade A, Border D (1975) Ultrastructural damage associated with reoxygenation of the anoxic myocardium. J Mol Cell Cardiol 7:315–324PubMedGoogle Scholar
  24. 24.
    Higgs EA, Moncada S, Vane JR (1978) Inflammatory effects of prostacyclin and 6-oxo-PGF in the rat paw. Prostaglandins 16:153–162PubMedGoogle Scholar
  25. 25.
    Higgs EA, Moncada S, Vane JR, Caen JP, Michel H, Tobelem G (1978) Effect of prostacyclin on platelet adhesion to rabbit arterial subendothelium. Prostaglandins 16:17–22PubMedGoogle Scholar
  26. 26.
    Holmes DR, Vlietstra RE, Smith HE (1984) Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from the PTCA registry of the National Heart, Lung and Blood Institute. Am J Cardiol 53:77c-81cPubMedGoogle Scholar
  27. 27.
    Kipper MS, Williams RJ (1983) Indium-111 white blood cells imaging. Clin Nucl Med 8:449–455PubMedGoogle Scholar
  28. 28.
    Laffel GL, Braunwald E (1984) Thrombolytic therapy: a new strategy for the treatment of acute myocardial infarction. N Engl J Med 311:710–717PubMedGoogle Scholar
  29. 29.
    Leinberger H, Suehiro GT, McNamara JJ (1979) Myocardial platelet trapping after coronary ligation in primates. J Surg Res 17:3–40Google Scholar
  30. 30.
    Levine JD, Lau W, Kwait G (1984) Leukotriene B4 produced hyperalgesia that is dependent on polymorphonuclear leukocytes. Science 225:743–745PubMedGoogle Scholar
  31. 31.
    Mitsos SE, Askew TE, Fantone JC, Kunkel SL, Abrams GD, Schork A, Luechesi BR (1986) Protective effects of N-z-mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in dog: evidence for the role of intracellular-derived free radicals. Circulation 73:1077–1086PubMedGoogle Scholar
  32. 32.
    Mullanc K, Moncada S (1982) The salvage of ischemic myocardium by BW755C in anesthetized dogs. Prostaglandins 24:255–260PubMedGoogle Scholar
  33. 33.
    Mullane KM, Read N, Salmon JA, Moncada S (1984) Role of leukocytes in acute myocardial infarction in anesthetized dogs: relationship of myocardial salvage by anti-inflammatory drugs. J Pharmacol Exp Ther 228:510–522PubMedGoogle Scholar
  34. 34.
    Otani H, Engelman RM, Rousou JA, Breyer RH, Lemeshow S, Das DK (1986) Cardiac performance during reperfusion improved by pretreatment with oxygen free-radical scavengers. J Thorac Cardiovasc Surg 91:290–295PubMedGoogle Scholar
  35. 35.
    Otani H, Engelman RM, Breyer RH, Rousou JA, Lemeshow S, Das DK (1986) Mepacrine, a phospholipase inhibitor: a potential tool for modifying myocardial reperfusion injury. J Thorac Cardiovasc Surg 92:247–254PubMedGoogle Scholar
  36. 36.
    Otani H, Engelman RM, Rousou JA, Breyer RH, Das DK (1986) Enhanced prostaglandin synthesis due to phospholipid breakdown in ischemic-reperfused myocardium. J Mol Cell Cardiol 18:953–961PubMedGoogle Scholar
  37. 37.
    Packham MA, Mustard JF (1980) Pharmacology of platelet-affecting drugs. Circulation G20 (Suppl V):V26-V41Google Scholar
  38. 38.
    Reimer KA, Jennings RB, Cobb FR, Murdock RH, Greenfield JC, Becker LC, Bulkley BH, Hutchins GM, Schwartz RP, Bailey KR, Passamani ER (1985) Animal models for protecting ischemic myocardium: results of the NHLBI cooperative study. Circ Res 56:651–665PubMedGoogle Scholar
  39. 39.
    Romson JL, Hook BG, Kunkel SL, Abrams GD, Schork MA, Lucchesi BR (1983) Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation 67:1016–1023PubMedGoogle Scholar
  40. 40.
    Romson JL, Hook BG, Rigot VH, Schork MA, Swanson DP, Lucchesi BR (1982) The effect of ibuprofen on accumulation of indium-111-labeled platelets and leukocytes in experimental myocardial infarction. Circulation 66:1002–1011PubMedGoogle Scholar
  41. 41.
    Rousou JA, Engelman RM, Anisimowiez L, Lemeshow S, Dobbs WA, Breyer RH, Das DK (1986) Metabolic enhancement of myocardial preservation during cardioplegic arrest. J Thorac Cardiovasc Surg 91:270–276PubMedGoogle Scholar
  42. 42.
    Stern W, Pullman ME (1983) Regulation of the composition and positioning of saturated and monoenoic fatty acids in phosphatidylcholine. J Biol Chem 258:11128–11135PubMedGoogle Scholar
  43. 43.
    Tillmanns H, Kubler (1984) What happens in the microcirculation? In: Hearsc DJ, Yellon DM (eds) Therapeutic approaches to myocardial infarct size limitation. Raven Press, New York, pp 107–124Google Scholar
  44. 44.
    Weksler BB, Marcus AJ, Jaffc EA (1977) Synthesis of prostaglandin I (prostacyclin) by cultured human and bovine endothelial cells. Proc Natl Acad Sci 74:3922–3926PubMedGoogle Scholar
  45. 45.
    Wildenthal K (1978) Lysosomal alteration in ischemic myocardium: result or cause of myocellular damage? J Mol Cell Cardiol 10:595–603PubMedGoogle Scholar
  46. 46.
    Yee ES, Price DC, Ahernet T, Ebert PA (1986) Intracoronary platelet aggregation. Pattern of deposition after ischemia, cardioplegia, and reperfusion. J Surg Res 40:499–503PubMedGoogle Scholar
  47. 47.
    Zweicr JL, Flaherty JT, Weisfeld ML (1987) Direct measurement of free radical generation following reperfusion of ischemic myocardium. Proc Natl Acad Sci 84:1404–1407PubMedGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag 1990

Authors and Affiliations

  • R. Clement
    • 1
  • D. K. Das
    • 1
  • R. M. Engelman
    • 2
  • H. Otani
    • 1
  • D. Bandhyopadhyay
    • 3
  • S. Hoory
    • 3
  • M. Antar
    • 4
  • J. A. Rousou
    • 2
  • R. H. Breyer
    • 2
  • M. R. Prasad
    • 1
  1. 1.Cardiovascular Division, Department of SurgeryUniversity of Connecticut School of MedicineFarmington
  2. 2.Department of SurgeryBaystate Medical CenterSpringfield
  3. 3.Department of RadiologyLong Island Jewish Medical CenterNew Hyde Park
  4. 4.Department of Nuclear MedicineVeterans Administration HospitalNewingtonUSA

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