Basic Research in Cardiology

, Volume 77, Issue 4, pp 411–422 | Cite as

Lack of thromboxane A2 involvement in the arrhythmias occurring during acute myocardial ischemia in dogs

  • S. E. Burke
  • M. J. Antonaccio
  • A. M. Lefer
Original Contributions

Summary

Coronary artery occlusion (CAO) followed by reperfusion of the ischemic myocardium has been associated with the onset of ventricular arrhythmias. It has been suggested that platelet aggregates in the ischemic area may release thromboxane A2 (TxA2) which may then be responsible for the arrhythmias that occur during reperfusion. To study this possibility, the effect of TxA2 synthetase inhibition on arrhythmias was examined in anesthetized dogs during occlusion and for 60 minutes following release. Imidazole (30 mg/kg) was infused intravenously for 10 minutes, followed by continuous infusion of 100 mg/kg/hr for 125 minutes. The left anterior descending coronary artery was occluded, 5 minutes after the initial dose, for 60 minutes. Three minutes after release of CAO, TxB2 concentrations were significantly higher in the arterial blood of vehicle-treated animals (2.06±0.53 pmoles/ml) than in either CAO + imidazole (0.66±0.16 pmoles/ml) or sham-CAO animals receiving imidazole (0.66±0.09 pmoles/ml). However, CAO dogs whether receiving imidazole or 0.9% NaCl generated a significantly greater number of ectopic beats during and after occlusion than sham-CAO animals. Therefore, release of TxA2 does not appear to be a major causative factor in the generation of reperfusion arrhythmias in dogs following coronary artery occlusion.

Key words

thromboxane B2 coronary artery occlusion imidazole reperfusion arrhythmias coronary blood flow 

Zusammenfassung

Koronarokklusion mit nachfolgender Reperfusion des ischämischen Myokards löst ventrikuläre Rhythmusstörungen aus. Es wurde vermutet, daß Plättchenaggregate im ischämischen Bereich Thromboxan A2 freigeben und daß diese Substanz für die während der Reperfusionsphase auftretenden Arrhythmien verantwortlich sein könnte. Um diese Möglichkeit zu untersuchen, wurde der Effekt einer Hemmung der Thromboxan-A2-Synthetase bei narkotisierten Hunden während der Arterienabklemmung und über 60 Minuten nach Öffnung des Verschlusses geprüft. Imidazol (30 mg/kg) wurde über 10 Minuten intravenös infundiert, gefolgt von einer kontinuierlichen Infusion von 100 mg/kg/h über einen Zeitraum von 125 Minuten. Der Ram. descendens der linken Koronararterie wurde, beginnend 5 Minuten nach der initialen Dosis, für 60 Minuten verschlossen. 3 Minuten nach Öffnung des Arterienverschlusses waren die Thromboxan-B2-Konzentrationen im Blut derjenigen Tiere, denen nur Lösungsmittel injiziert wurde, signifikant höher (2,06±0,35 pmoles/ml) als bei Tieren mit Okklusion+Imidazol (0,60±0,16 pmoles/ml) oder scheinoperierten Tieren, welche Imidazol erhielten (0,66±0,09 pmoles/ml). Jedoch traten bei den Hunden mit Okklusion, gleichgültig ob sie Imidazol oder 0,9%ige Kochsalzlösung erhielten, eine signifikant größere Zahl von ektopischen Schlägen während und nach der Okklusion auf als bei scheinoperierten Tieren. Somit scheint die Freisetzung von Thromboxan A2 kein wesentlicher Faktor bei der Entstehung von Arrhythmien in der Reperfusionsphase nach Koronararterienokklusion des Hundes zu sein.

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References

  1. 1.
    Balke, C. W., E. Kaplinsky, E. L. Michelson, M. Naito, L. S. Dreifus: Reperfusion ventricular tachyarrhythmias: Correlation with antecedent coronary artery occlusion tachyarrhythmias and duration of myocardial ischemia. Amer. Heart J.101, 449 (1981).CrossRefPubMedGoogle Scholar
  2. 2.
    Chignard, M., B. B. Vargaftig: Dog platelets fail to aggregate when they form aggregating substances upon stimulation with arachidonic acid. Europ. J. Pharmacol.38, 7 (1976).CrossRefGoogle Scholar
  3. 3.
    Chignard, M., B. B. Vargaftig: Synthesis of thromboxane A2 by non-aggregating dog platelets challenged with arachidonic acid or with prostaglandin H2. Prostaglandins14, 222 (1977).CrossRefPubMedGoogle Scholar
  4. 4.
    Coker, S. J., I. McA. Ledingham, J. R. Parratt, I. J. Zeitlin: Aspirin inhibits the early myocardial release of thromboxane B2 and ventricular ectopic activity following acute coronary artery occlusion in dogs. Brit. J. Pharmacol.72, 593 (1981).Google Scholar
  5. 5.
    Corbalan, R., R. L. Verrier, B. Lown: Differing mechanisms for ventricular vulnerability during coronary artery occlusion and release. Amer. Heart J.92, 223 (1976).PubMedGoogle Scholar
  6. 6.
    Ellis, E. F., O. Oelz, L. J. Roberts II, N. A. Payne, B. J. Sweetman, A. S. Nies, J. A. Oates: Coronary arterial smooth muscle contraction by a substance released from platelets: Evidence that it is thromboxane A2. Science193, 1135 (1976).PubMedGoogle Scholar
  7. 7.
    Hamberg, M., J. Svensson, B. Samuelsson: Thromboxanes: A new group of biologically active compounds derived from prostaglandin endoperoxides. Proc. Nat. Acad. Sci. USA72, 2994 (1975).PubMedGoogle Scholar
  8. 8.
    Harris, A. S., A. G. Rojas: The initiation of ventricular fibrillation due to coronary occlusion. Exp. Med. Surg.1, 105 (1943).Google Scholar
  9. 9.
    Hearse, D. J.: Cardioplegia: The protection of the myocardium during open heart surgery: A Review. J. Physiol. (Paris)76, 751 (1980).Google Scholar
  10. 10.
    Hirsh, P. D., L. D. Hillis, W. B. Campbell, B. G. Firth, J. T. Willerson: Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease. New Engl. J. Med.304, 685 (1981).PubMedGoogle Scholar
  11. 11.
    Lefer, A. M., E. F. Smith III, H. Araki, J. B. Smith, D. Aharony, D. A. Claremon, R. L. Magolda, K. C. Nicolaou: Dissociation of vasoconstriction and platelet aggregatory activities of thromboxane by carbocyclic thromboxane A2, a stable analog of thromboxane A2. Proc. Nat. Acad. Sci. USA77, 1706 (1980).PubMedGoogle Scholar
  12. 12.
    Lefer, A. M., J. B. Smith, K. C. Nicolaou: Cardiovascular actions of two thromboxane A2 analogs. In: Cardiovascular Physiology: Microcirculation and Capillary Exchange. Adv. Physiol. Sci., Vol. 7 (A. G. B. Kovách, J. Hamar and L. Szabó, eds.) pp. 91–98. Pergamon Press, (London 1981).Google Scholar
  13. 13.
    Levites, R., V. S. Banka, R. H. Helfant: Electrophysiologic effects of coronary occlusion and reperfusion. Observations of dispersion of refractoriness and ventricular automaticity. Circulation52, 760 (1975).PubMedGoogle Scholar
  14. 14.
    Lewy, R. I., J. B. Smith, M. J. Silver, J. Saia, P. Walinsky, L. Wiener: Detection of thromboxane B2 in peripheral blood of patients with Prinzmetal's Angina. Prostaglandins and Med.5, 243 (1979).CrossRefGoogle Scholar
  15. 15.
    Lewy, R. I., L. Wiener, P. Walinsky, A. M. Lefer, M. J. Silver, J. B. Smith: Thromboxane release during pacing-induced angina pectoris: Possible vasoconstrictor influence on the coronary vasculature. Circulation61, 1165 (1980).PubMedGoogle Scholar
  16. 16.
    Marooka, S., M. Kobayashi, T. Takahashi, Y. Takashima, M. Sakamoto, T. Shimamoto: Experimental ischemic heart disease — effects of synthetic thromboxane A2. Exp. Molec. Path.30, 449 (1979).CrossRefPubMedGoogle Scholar
  17. 17.
    Moncada, S., S. Bunting, K. Mullane, P. Thorogood, J. R. Vane, A. Raz, P. Needleman: Imidazole: A selective inhibitor of thromboxane synthetase. Prostaglandins13, 611 (1977).CrossRefPubMedGoogle Scholar
  18. 18.
    Penkoskie, P. A., B. E. Sobel, P. B. Corr: Disparate electrophysiological alterations accompanying dysrhythmia due to coronary occlusion and reperfusion in the cat. Circulation58, 1023 (1978).PubMedGoogle Scholar
  19. 19.
    Robertson, R. M., D. Robertson, G. C. Friesinger, S. Timmons J. Hawiger: Platelet aggregates in peripheral and coronary sinus blood in patients with spontaneous coronary artery spasm. Lancet1980/II, 829.Google Scholar
  20. 20.
    Sakai, K., T. Ito, K. Ogawa, H. Hashimoto, I. Enomoto, I. Kai, M. Ban, K. Minakuchi, T. Satake: Increased levels of prostaglandins and thromboxane after acute coronary occlusion in dogs. Japan. Circ. C.44, 658 (1980).Google Scholar
  21. 21.
    Schror, K., E. F. Smith III, M. Bickerton, J. B. Smith, K. C. Nicolaou, R. Magolda, A. M. Lefer: Preservation of ischemic myocardium by pinane thromboxane A2. Amer. J. Physiol.238, H87 (1980).PubMedGoogle Scholar
  22. 22.
    Schwartz, M. B., J. Hawiger, S. Timmons, G. C. Friesinger: Platelet aggregates in ischemic heart disease. Thromb. Hemostas.43, 185 (1980).Google Scholar
  23. 23.
    Smith, E. F. III, A. M. Lefer, J. B. Smith: Influence of thromboxane inhibition on the severity of myocardial ischemia in cats. Can. J. Physiol. Pharmacol.58, 294 (1980).PubMedGoogle Scholar
  24. 24.
    Smith, E. F. III, A. M. Lefer, D. Aharony, J. B. Smith, R. L. Magolda, D. Claremon, K. C. Nicolaou: Carbocyclic thromboxane A2: Aggravation of myocardial ischemia by a new synthetic thromboxane A2 analog. Prostaglandins21, 443 (1981).CrossRefPubMedGoogle Scholar
  25. 25.
    Smith, J. B., H. Araki, A. M. Lefer: Thromboxane A2, prostacyclin and aspirin: Effects on vascular tone and platelet aggregation. Circulation62 (Suppl. V), V19 (1980).PubMedGoogle Scholar
  26. 26.
    Sobel, B. E., P. B. Corr, A. K. Robison, R. A. Goldstein, F. X. Witkowski, M. S. Klein: Accumulation of lysophosphoglycerides with arrhythmogenic properties in ischemic myocardium. J. Clin. Invest.62, 546 (1978).PubMedGoogle Scholar
  27. 27.
    Szczeklik, A., R. J. Gryglewski, J. Musial, L. Grodzinska, M. Serwonska, E. Marcinkiewicz: Thromboxane generation and platelet aggregation in survivals of myocardial infarction. Thromb. Haemostas.40, 66 (1978).Google Scholar
  28. 28.
    Terashita, Z. I., H. Fukui, K. Nishikawa, M. Harata, S. Kikuchi: Coronary vasospastic action of thromboxane A2 in isolated, working guinea pig hearts. Europ. J. Pharmacol.53, 49 (1978).CrossRefGoogle Scholar
  29. 29.
    Wang, H.-H., P. S. Kulkarni, K. E. Eakins: Effects of prostaglandins and thromboxane A2 on the coronary circulation of adult dogs and puppies. Europ. J. Pharmacol.66, 31 (1980).CrossRefGoogle Scholar

Copyright information

© Dr. Dietrich Steinkopff Verlag 1982

Authors and Affiliations

  • S. E. Burke
    • 1
    • 2
  • M. J. Antonaccio
    • 1
    • 2
  • A. M. Lefer
    • 1
    • 2
  1. 1.Department of PharmacologySquibb Institute for Medical ResearchPrinceton
  2. 2.Department of Physiology, Jefferson Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA

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