Agents and Actions

, Volume 17, Issue 2, pp 220–228 | Cite as

Biochemical mechanisms in 5-hydroxytryptamine-induced human platelet aggregation

  • Fred de Clerck
  • Benoit Xhonneux
  • Ronny van de Wiele
Platelets and Thrombosis


The activation of human platelets by 5-hydroxytryptamine (5-HT) is not accompanied by detectable release of ATP or TXB2. The process is unaffected by cyclooxygenase, thromboxane synthetase or combined cyclooxygenase/lipoxygenase inhibition (suprofen, indomethacin, R19 091, dazoxiben, N.D.G.A., BW755C, esculetin), indicating the absence of involvement of arachidonic acid metabolites. Transmembrane Ca2+-entry blockers (flunarizine, nifedipine, nimodipine) have no effect either, indicating that the activator calcium released by 5-HT comes from intracellular stores. The 5-HT-induced platelet activation is inhibited by stimulators of adenylate cyclase (PGE1, PGE2, isoprenaline, adenosine) and inhibitors of cAMP phosphodiesterase (papaverine, anagrelide, RA233), indicating that also for this type of platelet activation cAMP behaves as a unidirectional, inhibitory regulator.


Indomethacin PGE1 Nifedipine Platelet Activation Nimodipine 
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  1. [1]
    H. Holmsen, Platelet activation and serotonin. InSerotonin and the Cardiovascular System, pp. 75–86 (Ed.P.M. Vanhoutte). Raven Press, New York, 1985.Google Scholar
  2. [2]
    J. Stoltz, Uptake and storage of serotonin by platelets. InSerotonin and the Cardiovascular System, pp. 37–42 (Ed.P.M. Vanhoutte). Raven Press, New York, 1985.Google Scholar
  3. [3]
    F. de Clerck, J.M. van Nueten andR.S. Reneman,Platelet-vessel wall interactions: implication of 5-hydroxytryptamine, Agents and Actions15, 612–626 (1984).PubMedGoogle Scholar
  4. [4]
    F. de Clerck, B. Xhonneux, J. Leysen andP.A.J. Janssen,Evidence for functional 5-HT 2 receptor sites on human blood platelets, Biochem. Pharamac.33, 2807–2811 (1984).CrossRefGoogle Scholar
  5. [5]
    F. de Clerck, B. Xhonneux, J.E. Leysen andP.A.J. Janssen,The involvement of 5-HT 2 receptor sites in the activation of cat platelets, Thromb. Res.33, 305–321 (1984).CrossRefPubMedGoogle Scholar
  6. [6]
    D. de Chaffoy De Courcelles, F. de Clerck, J.E. Leysen, H. van Belle andP.A.J. Janssen,Evidence that phospholipid turnover is the signal transducing system coupled to serotonin-S 2 receptor sites, J. Biol. Med., in press (1985).Google Scholar
  7. [7]
    J.W. Putney,Recent hypotheses regarding the phosphatidyl inositol effect, Life Sci.29, 1183–1194 (1981).CrossRefPubMedGoogle Scholar
  8. [8]
    P. Erne, H. Bühler, M. Affolter andE. Bürgisser,Excitatory and inhibitory modulation of intracellular free calcium in human platelets by hormones and drugs, Eur. J. Pharmac.91, 331–332 (1983).CrossRefGoogle Scholar
  9. [9]
    F. de Clerck andJ.L. David,Pharmacological control of platelet and red blood cell function in the microcirculation, J. Cardiovasc. Pharmac.4, 1388–1412 (1982).Google Scholar
  10. [10]
    M.B. Zucker andV.T. Nachmias,Platelet activation, Arteriosclerosis5, 2–18 (1985).PubMedGoogle Scholar
  11. [11]
    B.B. Vargaftig, M. Chignard, J.P. Le Benveniste,One, two, three or more pathways for platelet aggregation, Acta med. Scand. Suppl.642, 23–29 (1980).Google Scholar
  12. [12]
    B.B. Vargaftig, M. Chignard andJ. Benveniste,Present concepts on the mechanism of platelet aggregation, Biochem. Pharmac.30, 263–271 (1981).CrossRefGoogle Scholar
  13. [13]
    F. de Clerck, J.L. David andP.A.J. Janssen,Inhibition of 5-hydroxytryptamine-induced and-amplified human platelet aggregation by ketanserin (R 41 468), a selective 5-HT 2-receptor antagonist, Agents and Actions12, 388–397 (1982).PubMedGoogle Scholar
  14. [14]
    R.M. McMillan, D.E. MacIntyre andJ.L. Gordon,Simple, sensitive fluorimetric assay for malondialdehyde production by blood platelets, Thromb. Res.11, 425–428 (1977).CrossRefPubMedGoogle Scholar
  15. [15]
    S. Siegel,Non-Parametric Statistics for the Behavioral Sciences. McGraw-Hill, New York, 1954.Google Scholar
  16. [16]
    J.R. O'Brien,A comparison of platelet aggregation produced by seven compounds and a comparison of their inhibitors, J. clin. Pathol.17, 275–281 (1964).PubMedGoogle Scholar
  17. [17]
    R.J. Haslam,Role of adenosine diphosphate in the aggregation of human blood platelets by thrombin and fatty acids, Nature202, 765–768 (1964).PubMedGoogle Scholar
  18. [18]
    A.H. Drummond, Interactions of blood platelets with biogenic amines, uptake, stimulation and receptor binding. InPlatelets in Biology and Pathology — 1, pp. 203–239 (Ed.J.L. Gordon). North-Holland Publishing Company, Amsterdam, 1976.Google Scholar
  19. [19]
    D.C.B. Mills, I.A. Robb andG.C.K. Roberts,The release of nucleotides, 5-hydroxytryptamine and enzymes from human blood platelets during aggregation, J. Physiol.195, 715–729 (1968).PubMedGoogle Scholar
  20. [20]
    E.M. Huang andT.C. Detweiler,Reassessment of the evidence for the role of secreted ADP in biphasic platelet aggregation, J. lab. clin. Med.95, 59–68 (1960).Google Scholar
  21. [21]
    B. Nunn andP.D. Chamberlain,Further evidence against the validity of using an ADP-remaining enzyme system (CP/CPK) for demonstrating the role of secreted ADP in platelet activation, Thromb. Res.30, 19–26 (1983).CrossRefPubMedGoogle Scholar
  22. [22]
    J.M. Gerrard, J.G. White andD.A. Peterson,The platelet dense tubular system: its relationship to prostaglandin synthesis and calcium flux, Thromb. Haemost.40, 224–231 (1978).PubMedGoogle Scholar
  23. [23]
    C.E. Dutilh, E. Haddeman, J.A. Don andF. Tenhoor,The role of arachidonate lipoxygenase and fatty acids during irreversible blood platelet aggregation in vitro, Prostaglandins Med.6, 111–126 (1981).CrossRefPubMedGoogle Scholar
  24. [24]
    P. Massini, R. Käser-Glanzmann andE.F. Luscher,Movements of calcium ions and their role in the activation of platelets, Thromb. Haemost.40, 212–218 (1979).Google Scholar
  25. [25]
    E.F. Lüscher,Die intrazelluläre Regulation der Plättchenaktivität, Arzneim.-Forsch.33, 1362–1364 (1983).Google Scholar
  26. [26]
    G.C. Lebreton andR.J. Dinerstein,Effect of the calcium antagonist TMB-G on the intracellular calcium redistribution associated with platelet shape change, Thromb. Res.10, 521–523 (1977).CrossRefPubMedGoogle Scholar
  27. [27]
    W.G. Nayler,Calcium antagonists, Eur. Heart J.1, 225–237 (1980).PubMedGoogle Scholar
  28. [28]
    C.A. Bouvier,Calcium antagonists and platelet function, Arzneim.-Forsch.33, 1401–1405 (1983).Google Scholar
  29. [29]
    N.E. Owen andG.C. Lebreton,The involvement of calcium in epinephrine and ADP potentiation of human platelet aggregation, Thromb. Res.17, 855–863 (1980).CrossRefPubMedGoogle Scholar
  30. [30]
    M.J. Berridge, The interaction of cyclic nucleotides and calcium in the control of cellular activity. InAdvances in Cyclic Nucleotide Research, vol. 6, pp. 1–98 (EdsP. Greengard andG.A. Robinson). Raven Press, New York, 1975.Google Scholar
  31. [31]
    M.B. Feinstein, G.A. Rodan andL.S. Cutler, Cyclic AMP and calcium in platelet function. InPlatelets in Biology and Pathology — 1, pp. 437–472 (Ed.J.C. Gordon). Elsevier/North-Holland Biomedical Press, Amsterdam, 1981.Google Scholar
  32. [32]
    J. Vermylen, P.N. Badenhorst, H. Deckmyn andJ. Arnout, Normal mechanisms of platelet function. InPlatelet Disorders, Clinics in Haematology, vol. 12, pp. 107–151 (EdsL.A. Harber andT.S. Zimmerman). 1983.Google Scholar
  33. [33]
    J.W.D. McDonald andR.K. Stuart,Regulation of cyclic AMP levels and aggregation in human platelets by prostaglandin E 1, J. lab. clin. Med.81, 838–849 (1973).PubMedGoogle Scholar
  34. [34]
    D.C.B. Mills, Factors influencing the adenylate cyclase system in human blood platelets. InPlatelets and Thrombosis, pp. 45–67 (EdsS. Sherry andA. Scriabine). Urban & Schwarzenberg, Munchen, 1974.Google Scholar
  35. [35]
    R. Haslam, M.M.L. Davidson, J.V. Desjardins, J.E.B. Fox andJ.A. Lynham, Factors affecting the formation and actions of cyclic AMP in blood platelets. InProstaglandin-Immuno-Pharmacology — 4, pp. 75–85 (Ed.B.B. Vargaftig). Pergamon Press, New York, 1979.Google Scholar
  36. [36]
    P.D. Zieve andW.B. Greenough,Adenyl cyclase in human platelets: activity and responsiveness, Biochem. biophys. Res. Commun.35, 462–466 (1969).CrossRefPubMedGoogle Scholar
  37. [37]
    E. Salzman,Cyclic AMP and platelet function, New Engl. J. Med.286, 358–363 (1982).Google Scholar
  38. [38]
    K.H. Jakobs, E. Böhme andS. Mocikat,Cyclic GMP formation in human platelets, Naunyn-Schmiedeberg's Archs. Pharmac.282, R40 (1974).Google Scholar
  39. [39]
    K.C. Agarwal andM. Steiner,Effect of serotonin on cyclic nucleotides of human platelets, Biochem. biophys. Res. Commun.69, 462–469 (1976).CrossRefPubMedGoogle Scholar
  40. [40]
    D.C.B. Mills andJ.B. Smith,The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3′∶5′-cyclic monophosphate in platelets, Biochem. J.121, 185–196 (1971).PubMedGoogle Scholar
  41. [41]
    F. Markwardt andH. Hoffmann,Effects of papaverine derivatives on cyclic AMP phosphodiesterase of human platelets, Biochem. biophys. Res. Commun.19, 2519–2520 (1970).Google Scholar
  42. [42]
    S.S. Tang andM.M. Frojmovic,Inhibition of platelet function by antithrombotic agents which selectively inhibit low-Km cyclic 3′,5′-adenosine-monophosphate phosphodiesterase, J. lab. clin. Med.95, 241–257 (1980).PubMedGoogle Scholar
  43. [43]
    S.C.T. Lam, M.A. Guccione, M.A. Packham andJ.F. Mustard,Effect of cAMP phosphodiesterase inhibitors of ADP-induced shape change, cAMP and nucleoside diphosphokinase activity of rabbit platelets, Thromb. Haemost.47, 90–95 (1982).PubMedGoogle Scholar
  44. [44]
    J. Kloeze,Relationship between chemical structure and platelet-aggregation activity of prostaglandins, Biochim. biophys. Acta187, 285–292 (1969).PubMedGoogle Scholar
  45. [45]
    E. Salzman, Platelet aggregation and cyclic AMP. InPlatelets, Drugs and Thrombosis, pp. 35–42 (EdsJ. Hirsh, J.F. Cade, A.S. Gallus andE. Schönbaum). S. Karger, Basel, 1975.Google Scholar
  46. [46]
    J.J. Bruno, L.A. Taylor andM.J. Droller,Effects of prostaglandin E 2 on human platelet adenyl cyclase and aggregation, Nature251, 721–723 (1974).PubMedGoogle Scholar
  47. [47]
    R. Ryo,Studies on the role of cyclic 3′,5′-adenosine monophosphate in platelet functions with special reference to aggregation and serotonin release of human blood platelets, Acta Haem. Jap.39, 85–96 (1976).Google Scholar
  48. [48]
    H. Shio andP. Ramwell,Effect of prostaglandin E 2 and aspirin on the secondary aggregation of human platelets, Nature236, 45–46 (1972).Google Scholar
  49. [49]
    T.Y. Wang, C.V. Hussey andJ.C. Garances,Effects of dibutyryl cyclic adenosine monophosphate and prostaglandin E 1 in platelet aggregation and shape changes, Am. J. clin. Pathol.67, 362–367 (1977).PubMedGoogle Scholar
  50. [50]
    A.K. Sinha andR.W. Colman,Prostaglandin E 1 inhibits platelet aggregation by a pathway independent of adenosine 3′:5′-monophosphate, Science200, 202–203 (1978).PubMedGoogle Scholar
  51. [51]
    D.J. Boullin, A.R. Green andK.S. Price,The mechanism of adenosine diphosphate induced platelet aggregation: binding to platelet receptor and inhibition of binding and aggregation by prostaglandin E 1, J. Physiol.221, 415–426 (1972).PubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag 1985

Authors and Affiliations

  • Fred de Clerck
    • 1
  • Benoit Xhonneux
    • 1
  • Ronny van de Wiele
    • 1
  1. 1.Laboratory of Haematology, Department of Life SciencesJanssen Pharmaceutica Research LaboratoriesBeerseBelgium

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