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Effects of trimetazidine on in vivo coronary arterial platelet thrombosis

  • Experimental Pharmacology
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Summary

We used Folts' model of critical coronary artery stenosis with endothelial damage, which measures platelet-rich thrombus accumulation from cyclic flow reductions (CFRs). This paper reports results applied to trimetazidine, a member of the piperazine group. Trimetazidine at a dose of 1 mg/kg completely abolished CFRs caused by accumulating thrombus in the circumflex coronary artery in 4 of 8 open-chest anesthetized beagles. More trimetazidine (up to 5 mg/kg) abolished CFRs in two more and attenuated them in the remaining two dogs. There were no systemic hemodynamic effects observed. Adrenaline was then infused to stimulate platelet activation. At a rate of 0.4 µg/kg/min, CFRs were restored in one dog only. Adrenaline given at 1.6 µg/kg/min resulted in restoration or increase in the slope of CFRs in all animals. A further six nonoperated dogs were anesthetized and given trimetazidine 3 mg/kg. Routine coagulation studies were not altered. However, aspirin 5 mg/kg significantly increased bleeding time, whereas trimetazidine alone did not. These findings suggest that trimetazidine is effective in preventing intracoronary platelet aggregation in this model. Because of its demonstrated sparing of coagulation factors and its lack of effect on bleeding time, the cause is unlikely to be inhibition of the fibrinogen or thrombin receptors, or interference with arachidonic acid metabolism.

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References

  1. Lewis HD, Davis JW, Archibald DG. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration cooperative study.N Engl J Med 1985;313:1369–1375.

    PubMed  Google Scholar 

  2. Bush LR, Effects of the serotonin antagonists, cyproheptadine, ketanserin and mianserin, on cyclic flow reductions in stenosed canine coronary arteries.J Pharmacol Exp Ther 1987;240:674–682.

    PubMed  Google Scholar 

  3. Ashton JH, Ogletree ML, Michel IM, et al. Cooperative mediation by serotonin S2 and thromboxane A2/prostaglandin H2 receptor activation of cyclic flow variations in dogs with severe coronary artery stenoses.Circulation 1987;76:952–959.

    PubMed  Google Scholar 

  4. Eidt JF, Allison P, Noble S, et al. Thrombin is an important mediator of platelet aggregation in stenosed canine coronary arteries with endothelial injury.J Clin Invest 1989;84:18–27.

    PubMed  Google Scholar 

  5. Coller BS, Folts JD, Scudder LE, et al. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor in an experimental animal model.Blood 1986;68:783–786.

    PubMed  Google Scholar 

  6. Yasuda T, Gold HK, Leinbach RC, et al. Kistrin, a polypeptide platelet GP IIb/IIIa receptor antagonist enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation.Circulation 1991;83:1038–1047.

    PubMed  Google Scholar 

  7. Yao S-K, Ober JC, McNatt J, et al. ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothelium-injured canine coronary arteries.Circ Res 1992;70:39–48.

    PubMed  Google Scholar 

  8. Charo IF, Feinman RD, Detwiler TC. Inhibition of platelet secretion by an antagonist of intracellular calcium.Biochem Biophys Res Commun 1976;72:1462–1467.

    PubMed  Google Scholar 

  9. Feinstein MB. Release of intracellular membrane-bound calcium precedes the onset of stimulus-induced exocytosis in platelets.Biochem Biophys Res Commun 1980;93:593–600.

    PubMed  Google Scholar 

  10. Wood AJ, Isted K, Hynd J, et al. Mioflazine, a potentially protective drug against ischaemic damage: A study in dogs.Eur Heart J 1985;6:695–701.

    PubMed  Google Scholar 

  11. Maridonneau-Parini I, Harpey C. Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells.Br J Clin Pharmacol 1985;20:148–151.

    PubMed  Google Scholar 

  12. Higuchi H, Hayashi M, Sano I, et al. Effects of trimetazidine granules (Vastarel F) in platelet adhesiveness and aggregation in patients with ischemic heart disease.J Nissei Hosp 1981;3:89–95.

    Google Scholar 

  13. Folts JD, Rowe GC. Cyclic reductions in coronary blood flow in coronary arteries with partial obstruction and their inhibition with aspirin (abs).Fed Proc 1974;33:413.

    Google Scholar 

  14. Folts, JD, Gallagher K, Rowe GG. Blood flow reductions in stenosed canine coronary arteries: vasospasm or platelet aggregation.Circulation 1982;65:248–255.

    PubMed  Google Scholar 

  15. Michaelides AP, Vysoulis GP, Bonoris PE, et al. Beneficial effects of trimetazidine in patients with stable angina under beta-blockers.Cardiovasc Drugs Ther 1987;1:268.

    Google Scholar 

  16. Brochier M, Demange J, Ducloux G, et al. Therapeutic value of a combination of trimetazidine and a calcium antagonist for the treatment of chronic artery disease.Presse Med 1986;15:1783–1787.

    PubMed  Google Scholar 

  17. Torr S, Noble MIM, Folts JD. Inhibition of acute platelet thrombus formation in stenosed canine coronary arteries by specific serotonin 5HT2 receptor antagonist ritanserin.Cardiovasc Res 1990;24:464–470.

    Google Scholar 

  18. Keller JW, Folts JD. Relative effects of cigarette smoke and ethanol on acute platelet thrombus formation in stenosed canine coronary arteries.Cardiovasc Res 1988;22:73–78.

    PubMed  Google Scholar 

  19. Cox B, McAuliffe SJG, Moors JA, et al. The effects of adrenaline and 5-hydroxytryptamine on the rate of formation of platelet thrombi in a stenosed coronary artery of the anaesthetised dog (abstract).J. Physiol (London) 1991;438:169 P.

    Google Scholar 

  20. Bush LR, Shebuski RJ. In vivo models of arterial thrombosis and thrombolysis.FASEB J 1990;4:3087–3098.

    PubMed  Google Scholar 

  21. Jergens AE, Turrentine MA, Kraus KH, et al. Buccal mucosal bleeding times of healthy dogs and of dogs in various pathologic states, including thrombocytopenia, uremia, and von Willebrand's disease.Am J Vet Res 1987;48:1337–1342.

    PubMed  Google Scholar 

  22. Babson SR, Babson AL. Development and evaluation of a disposable device for performing simultaneous duplicate bleeding time determinations.Am J Clin Pathol 1978;70:406–408.

    PubMed  Google Scholar 

  23. Young M, Hintze TH, Vatner SF. Correlation between cardiac performance and plasma catecholamine levels in conscious dogs.Am J Physiol 1985;248:H82-H88.

    PubMed  Google Scholar 

  24. Timour Q, Goupit P, Lang J, et al. Anti-anginal effects of trimetazidine: mechanisms (abstract). Xth International Congress on Pharmacology, Sydney, Australia, 1987, p 648.

  25. Folts JD, Crowell EM, Rowe CG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin.Circulation 1976;54:365–370.

    PubMed  Google Scholar 

  26. Hill DS, Smith SR, Folts JD. The rabbit as a model for carotid artery stenosis, and periodic acute thrombosis (abstr).Fed Proc 1987;46:421.

    Google Scholar 

  27. Folts JD, Smith SO. Platelet thrombus formation in stenosed monkey carotid arteries: inhibited with aspirin, restored with epinephrine (abstr).J Am Coll Cardiol 1985;5:468.

    Google Scholar 

  28. Rao GHR, Escolar G, White JG. Epinephrine reverses the inhibitory influence of aspirin on platelet-vessel wall interactions.Thromb Res 1986;44:65–74.

    PubMed  Google Scholar 

  29. Yao S-K, Rosolowsky M, Anderson HV, et al. Combined thromboxane A2 synthetase inhibition and receptor blockade are effective in preventing spontaneous and epinephrine-induced canine coronary cyclic flow variations.J Am Coll Cardiol 1990;16:705–713.

    PubMed  Google Scholar 

  30. Ashton JH, Golino P, McNatt JM, et al. Serotonin S2 and thromboxane A2-prostaglandin H2 receptor blockade provide protection against epinephrine-induced cyclic flow variations in severely narrowed canine coronary arteries.J Am Coll Cardiol 1989;13:755–763.

    PubMed  Google Scholar 

  31. Shirahase H, Suzuki Y, Osumi S, et al. Inhibitory effects of trimetazidine dihydrochloride on aggregation, serotonin release and malondialdehyde production in rabbit platelets.Jpn J Pharmacol 1988;47:29–34.

    PubMed  Google Scholar 

  32. Eidt JF, Ashton J, Golino P, et al. Treadmill exercise promotes cyclic alterations in coronary blood flow in dogs with coronary artery stenoses and endothelial injury.J Clin Invest 1989;84:517–527.

    PubMed  Google Scholar 

  33. Yao S-K, McNatt J, Anderson V, et al. Thrombin inhibition enhances tissue-type plasminogen activator-induced thrombolysis and delays reocclusion.Am J Physiol 1992;262:H374-H379.

    PubMed  Google Scholar 

  34. Yasuda T, Gold HK, Yaoita H, et al. Comparative effects of aspirin, a synthetic thrombin inhibitor and a monoclonal antiplatelet glycoprotein IIb/IIIa antibody on coronary artery reperfusion, reocclusion and bleeding with recombinant tissue-type plasminogen activator in a canine preparation.J Am Coll Cardiol 1990;16:714–722.

    PubMed  Google Scholar 

  35. Kerins DM, Roy L, Kunitada S, et al. Pharmacokinetics of tissue-type plasminogen activator during acute myocardial infarction in men. Effect of a prostacyclin analogue.Circulation 1992;85:526–532.

    PubMed  Google Scholar 

  36. Kober G, Buck T, Sievert H, et al. Direct anti-ischemic effect of trimetazidine during coronary angioplasty (PTCA) (abstract).Circulation 1990;82(Suppl 111):302.

    PubMed  Google Scholar 

  37. Belcher PR, Drake-Holland AJ, Hynd JW, et al. Dispersion of coronary artery thrombi by antagonism of platelet serotonin receptor in the dog.Cardiovasc Res 1992;26:292–296.

    PubMed  Google Scholar 

  38. Morishima Y, Tanaka T, Watanabe K, et al. Prevention by DV-7028, a selective 5-HT2 receptor antagonist, of the formation of coronary thrombi in dogs.Cardiovasc Res 1991;25:727–730.

    PubMed  Google Scholar 

  39. Golino P, Ashton JH, Buja LM, et al. Local platelet activation causes vasoconstriction of large epicardial canine coronary arteries in vivo.Circulation 1989;79:154–166.

    PubMed  Google Scholar 

  40. Benedict CR, Mathew B, Rex KA, et al. Correlation of plasma serotonin changes with platelet aggregation in an in vivo dog model of spontaneous occlusive coronary thrombus formation.Circ Res 1986;58:58–67.

    PubMed  Google Scholar 

  41. Lavanchy N, Martin J, Rossi A. Anti-ischemic effects of trimetazidine:31P-NMR spectroscopy in the isolated rat heart.Arch Int Pharmacodyn 1987;286:97–110.

    PubMed  Google Scholar 

  42. Garnier D, Roulet MJ. Vasoactivity of trimetazidine on guinea-pig isolated ductus arteriosus.Br J Pharmacol 1985;84:517–524.

    PubMed  Google Scholar 

  43. Harpey C, Clauser P, Labrid C, et al. Trimetazidine, a cellular anti-ischemic agent.Cardiovasc Drug Rev 1989;6:292–312.

    Google Scholar 

  44. Gevers W. Generation of protons by metabolic processes in heart cells.J Mol Cell Cardiol 1977;9:867–874.

    PubMed  Google Scholar 

  45. Kiyosue T, Nakamura S, Arita M. Effects of trimetazidine on action potentials and membrane currents of guinea-pig ventricular myocytes.J Mol Cell Cardiol 1986;18:1301–1311.

    PubMed  Google Scholar 

  46. Eidt JF, Ashton J, Golino P, et al. Treadmill exercise promotes cyclic alterations in coronary blood flow in dogs with coronary artery stenoses and endothelial injury.J Clin Invest 1989;84:517–527.

    PubMed  Google Scholar 

  47. Dodds WJ. Platelet function in animals: species specificities. In: de Gaetano G, Garattini S, eds.Platelets: a multidisciplinary approach. New York: Raven Press, 1978;45–59.

    Google Scholar 

  48. Packham MA, Kinlough-Rathbone RL, Mustard JF. Thromboxane A2 causes feedback amplification involving extensive thromboxane A2 formation on close contact of human platelets in media with a low concentration of ionized calcium.Blood 1987;70:647–651.

    PubMed  Google Scholar 

  49. Eichhorn EJ, Grayburn PA, Willard JE, et al. Spontaneous alterations in coronary blood flow velocity before and after coronary angioplasty in patients with severe angina.J Am Coll Cardiol 1991;17:43–52.

    PubMed  Google Scholar 

  50. van den Berg EK, Schmitz JM, Benedict CR, et al. Transcardiac serotonin concentration is increased in selected patients with limiting angina and complex coronary lesion morphology.Circulation 1989;79:116–124.

    PubMed  Google Scholar 

  51. Hirsh PD, Hillis LD, Campbell WB, et al. Release of prostaglandins and thromboxane into the coronary circulation in patients with ischemic heart disease.N Engl J Med 1981;304:685–691.

    PubMed  Google Scholar 

  52. Jin L, Yan XW, Xu SH. Platelet functions in patients with acute myocardial infarction.Chung-Hua Hsin Hsueh Kuan Ping Tsa Chih 1989;17:275–278.

    PubMed  Google Scholar 

  53. Apprill P, Schmitz JM, Campbell WB, et al. Cyclic blood flow variations induced by platelet-activating factor in stenosed canine coronary arteries despite inhibition of thromboxane synthetase, serotonin receptors, and α-adrenergic receptors.Circulation 1985;72:397–405.

    PubMed  Google Scholar 

  54. Torr SR, Haskel EJ, Von Voigtlander PF, et al. Inhibition of cyclic flow variations and reocclusion after thrombolysis in dogs by a novel antagonist of platelet-activating factor.J Am Coll Cardiol 1991;18:1804–1810.

    PubMed  Google Scholar 

  55. Golino P, Piscione F, Willerson JT, et al. Divergent effects of serotonin on coronary artery dimensions and blood flow in patients with coronary atherosclerosis and control patients.N Engl J Med 1991;324:641.

    PubMed  Google Scholar 

  56. Woodman OL. Enhanced coronary vasoconstrictor responses to 5-hydroxytryptamine in the presence of a coronary artery stenosis in anaesthetized dogs.Br J Pharmacol 1990;100:153–157.

    PubMed  Google Scholar 

  57. Wright L, Homans DC, Laxson DD, et al. Effect of serotonin and thromboxane A2 on blood flow through moderately well developed coronary collateral vessels.J Am Coll Cardiol 1992;19:687–693.

    PubMed  Google Scholar 

  58. Bove AA, Dewey JD. Effects of serotonin and histamine on proximal and distal coronary vasculature in dogs: comparison with alpha-adrenergic stimulation.Am J Cardiol 1983;52:1333–1339.

    PubMed  Google Scholar 

  59. Brum JM, Sufan Q, Lane G, et al. Increased vasoconstrictor activity of proximal coronary arteries with endothelial damage in intact dogs.Circulation 1984;70:1066–1073.

    PubMed  Google Scholar 

  60. Chilian WM, Dellsperger KC, Layne SM, et al. Effects of atherosclerosis on the coronary microcirculation.Am J Physiol 1990;258:H529-H539.

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Academic Unit of Cardiovascular Medicine, Charing Cross and Westminster Medical School, 17 Horseferry Road, SW1P 2AR, London, England

    Philip R. Belcher MB (FRCS), Angela J. Drake-Holland, John W. Hynd & Mark I. M. Noble

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  1. Philip R. Belcher MB
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  2. Angela J. Drake-Holland
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  3. John W. Hynd
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  4. Mark I. M. Noble
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Belcher, P.R., Drake-Holland, A.J., Hynd, J.W. et al. Effects of trimetazidine on in vivo coronary arterial platelet thrombosis. Cardiovasc Drug Ther 7, 149–157 (1993). https://doi.org/10.1007/BF00878324

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