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Purines and Regulation of Platelet Activation

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Purines and Myocardial Protection

Part of the book series: Developments in Cardiovascular Medicine ((DICM,volume 181))

Abstract

Purines play key roles in platelet physiological regulatory processes (1–3). Human platelets in comparison with human erythrocytes and leukocytes, contain greater concentrations of adenine nucleotides (4,5), which are distributed between the metabolic and storage pools (5–10). During the induction of platelet aggregation by an agent such as thrombin or collagen, the storage pool nucleotides (principally ADP) as well as other vasoactive agents of the storage granules (e.g. serotonin, Ca2+) are released into the plasma (11,12). Platelet aggregation is strongly inhibited by other adenine nucleotides, adenosine 5′-tetraphosphate (AP4) (13,14), ATP (13–15), AMP (13,14,16,17), and adenosine (18–20). Adenosine is continuously produced in the body by many tissues including the vascular endothelium (21), brain, heart (22) and platelets (23). However, only low amounts of adenosine (100 to 300 nM) (23,24) are seen in human plasma due to its rapid cellular uptake and metabolism primarily by adenosine deaminase and adenosine kinase (25,26). Recent studies have shown that even these low plasma adenosine levels contribute greatly in the physiological regulatory process of platelet function (23,27,28). In addition, plasma adenosine plays an important role in the antiplatelet activity of cAMP phosphodiesterase inhibitors (29), forskolin (30), and nitric oxide [Maddali and Agarwal, unpublished results]. Theophylline and caffeine, which act as adenosine receptor antagonists, produce stimulation of platelet aggregation in human PRP with adenosine (27,28).

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References

  1. Born GVR. The breakdown of adenosine triphosphate in blood platelets during clotting. J Physiol 1956;133:61–62.

    PubMed  CAS  Google Scholar 

  2. Holmsen H. Platelet metabolism and activation. Semin Hematol 1985;22:219–240.

    PubMed  CAS  Google Scholar 

  3. Agarwal KC. Platelet aggregation and inhibitors. Principles of Cell Adhesion. In Richardson PD, Steiner M, editors. CRC Press, Boca Raton, FL, 1994. (In press)

    Google Scholar 

  4. Scholar EM, Brown PR, Parks RE Jr, Calabresi P. Nucleotide profiles of the formed elements of human blood determined by high-pressure liquid chromatography. Blood 1973;41:927–936.

    PubMed  CAS  Google Scholar 

  5. Agarwal KC, Parks RE Jr. Adenosine analogs and human platelets: effects on nucleotide pools and the aggregation phenomenon. Biochem Pharmacol 1975;24:2239–2248.

    Article  PubMed  CAS  Google Scholar 

  6. Mills DCB, Thomas DP. Blood platelet nucleotides in man and other species. Nature 1969;222:991–992.

    Article  PubMed  CAS  Google Scholar 

  7. Holmsen H, Storm E, Day HJ. Determination of ATP and ADP in blood platelets. Analyt Biochem 1972;46:489–501.

    Article  PubMed  CAS  Google Scholar 

  8. Holmsen H, Weiss HJ. Further for a deficient pool of adenine nucleotides in platelets from some patients with thrombocytopathia “storage pool disease.” Blood 1972;39:197–209.

    PubMed  CAS  Google Scholar 

  9. D’Souza L, Glueck HI. Measurement of nucleotide pools in platelets using high pressure liquid chromatography. Thromb Haemost 1977;38:990–1000.

    PubMed  Google Scholar 

  10. Reimers H-J. Adenine nucleotides in blood platelet. Platelets Physiology and Pharmacology. In Longenecker GL, editor. Academic Press, Orlando, FL, 1985;85–112.

    Google Scholar 

  11. Holmsen H, Weiss HJ. Secretable storage pools in platelets, Annu Rev Med 1979;30:119–134.

    Article  PubMed  CAS  Google Scholar 

  12. White JG. The dense bodies of human platelets. The Platelet Amine Storage Granule. In Meyers KM, Barnes CD, editors. CRC Press, Boca Raton, FL, 1992;l–27.

    Google Scholar 

  13. Harrison MJ, Brossmer R. Inhibition of ADP-induced platelet aggregation by adenosine tetraphosphate. Thromb Haemost 1976;36:388–391.

    PubMed  CAS  Google Scholar 

  14. Agarwal KC, Haskel EJ, Parks RE Jr. Effects of adenosine analogs and adenine nucleotides on adenosine 5′-diphosphate-induced rat platelet aggregation. Biochem Pharmacol 1980;29:1799–1805.

    Article  PubMed  CAS  Google Scholar 

  15. Macfarlane DE, Mills DCB. The effects of ATP on platelets: evidence against the central role of released ADP in primary aggregation. Blood 1975;46:309–320.

    PubMed  CAS  Google Scholar 

  16. Rozenberg MC, Holmsen H. Adenine nucleotide metabolism of blood platelets. II. Uptake of adenosine and inhibition of ADP-induced platelet aggregation. Biochim Biophys Acta 1968;342–352.

    Google Scholar 

  17. Packham MA, Guccione MA, Perry DW, Kinlough-Rathbone RL, Mustard JF. AMP inhibition of reactions of ADP with washed platelets from humans and rabbits. Am J Physiol 1972;223:419–424.

    PubMed  CAS  Google Scholar 

  18. Agarwal KC, Parks RE Jr, Townsend L. Adenosine analogs and human platelets - II. Inhibition of ADP-induced aggregation by carbocyclic adenosine and imidazole-ring modified analogs. Significance of alterations in the nucleotide pools. Biochem Pharmacol 1979;28:501–510.

    Article  PubMed  CAS  Google Scholar 

  19. Haslam RJ, Cusack NJ. Blood platelet receptors for ADP and adenosine. Purinergic receptors. In Burnstock G, editor. Chapman and Hall, London, 1981, 223–285.

    Google Scholar 

  20. Agarwal KC. Adenosine and platelet function. Role of Adenosine in Cerebral Metabolism and Blood Flow. In Stefanovich V, Okyayuz-Baklouti I, editors. VNU Science Press BV, Germany, 1988;107–124.

    Google Scholar 

  21. Nées S, Gerlach E. Adenine nucleotide and adenosine metabolism in cultured coronary endothelial cells. Regulatory Functions of Adenosine. Berne RM, Rail TW, Rubio R, editors. Martinus Nijhoff Publishers, The Hague, 1983;347–360.

    Google Scholar 

  22. Berne RM, Winn HR, Knabb RM, Ely SW, Rubio R. Blood flow regulation by adenosine in heart, brain and skeletal muscle. Regulatory Functions of Adenosine. Berne RM, Rail TW, Rubio R, editors. Martinus Nijhoff Publishers, The Hague, 1983;293–317.

    Google Scholar 

  23. Agarwal KC. Modulation of platelet functions by plasma adenosine. Role of Adenosine and Adenine Nucleotides in the Biological System. Imai S, Nakazawa M, editors. Elsevier Science Publishers, Amsterdam, 1991;457–468.

    Google Scholar 

  24. Sollevi A, Torssell L, Owall A, Edlund A, Lagerkranser M. Levels and cardiovascular effects of adenosine in humans. Topics and Perspectives in Adenosine Research. In Gerlach E, Backer BF, editors. Springer-Verlag, Heidelberg, 1987;559–613.

    Google Scholar 

  25. Dawicki DD, Agarwal KC, Parks RE Jr. Role of adenosine uptake and metabolism by blood cells in the antiplatelet actions of dipyridamole, dilazep and nitrobenzylthioinosine. Biochem Pharmacol 1985;34:3965–3972.

    Article  PubMed  CAS  Google Scholar 

  26. Dawicki DD, Agarwal KC, Parks RE Jr. Adenosine metabolism in human whole blood: Effects of nucleoside transport inhibitors and phosphate concentration. Biochem Pharmacol 1988;37:621–626.

    Article  PubMed  CAS  Google Scholar 

  27. Agarwal KC. Modulation of vasopressin actions on human platelets by plasma adenosine and theophylline: gender differences. J Cardiovasc Pharmacol 1993;1012–1018.

    Google Scholar 

  28. Agarwal KC, Clarke E, Rounds S, Parks RE Jr, Huzoor-Akbar. Platelet-activating factor (PAF)-induced platelet aggregation: modulation by plasma adenosine and methylxanthines. Biochem Pharmacol, 1994. (In press)

    Google Scholar 

  29. Agarwal KC, Buckley RS, Parks RE Jr. Role of plasma adenosine in the antiplatelet action of HL-725, a potent inhibitor of cAMP phosphodiesterase: species differences. Thromb Res 1987;47:191–200.

    Article  PubMed  CAS  Google Scholar 

  30. Agarwal KC, Zielinski BA, Maitra RS. Significance of plasma adenosine in the antiplatelet activity of forskolin: Potentiation by dipyridamole and dilazep. Thromb Haemost 1989;61:106–110.

    PubMed  CAS  Google Scholar 

  31. Holmsen H. Platelet metabolism and activation. Sem Haematol 1985;22:219–240.

    CAS  Google Scholar 

  32. Flodgaard H, Klenow H. Abundant amounts of diadenosine 5′,5′”- P1 –P4 -tetraphosphate are present and releasable, but metabolically inactive in human platelets. Biochem J 1982;208:737–742.

    PubMed  CAS  Google Scholar 

  33. Luthje J, Ogilvie A. The presence of diadenosine 5′,5′”-P1pP3- triphosphate (Ap3A) in human platelets. Biochem Biophys Res Commun 1983;115:253–260.

    Article  PubMed  CAS  Google Scholar 

  34. Luthje J, Ogilvie A. Diadenosine triphosphate (ApjA) mediates human platelet aggregation by liberation of ADP. Biochem Biophys Res Commun 1984;1185:704–709.

    Article  Google Scholar 

  35. Harrison M, Brossmer R, Goody R. Inhibition of platelet aggregation and the platelet release reaction by, diadenosine poly- phosphates. FEBS Letters 1975;54:57–60.

    Article  PubMed  CAS  Google Scholar 

  36. Day HJ, Holmsen H. Platelet nucleotide “Storage pool defciency” in thrombocytopenic absent radius syndrome. J Am Med Assoc 1972;221:1053–1054.

    Article  CAS  Google Scholar 

  37. Weiss HJ. Congenital disorders of platelet function. Sem Hematol 1980;17:228–241.

    CAS  Google Scholar 

  38. Meyers KM, Menard M. Platelet storage pool deficiency. The Platelet Amine Storage Granule. In Meyers KM, Barnes CD, editors, CRC Press, Boca Raton, FL, 1992;149–195.

    Google Scholar 

  39. Weiss HJ, Chervenick PA, Zalusky R, Factor A. A familial defect in platelet function associated with impaired release of adenosine diphosphate. N Engl J Med 1969;281:1265–1270.

    Article  Google Scholar 

  40. Holmsen H, Weiss HJ. Hereditary defect in the platelet release reaction caused by a deficiency in the storage pool of platelet adenine nucleotides. Br J Haemaotol 1970;19:643–649.

    Article  CAS  Google Scholar 

  41. Weiss HJ, Tschopp T, Brand H, Rogers J. Studies on platelet 5-hydroxytryptamine (serotonin) in patients with storage-pool disease and albinism. J Clin Invest 1974;54:421–432.

    Article  PubMed  CAS  Google Scholar 

  42. Hellem AJ. The adhesiveness of human platelets in vitro. Scand J Clin Lab Invest 1960;12(Suppl 51):1–117.

    PubMed  Google Scholar 

  43. Gaarder A, Jonsen J, Laland S, Hellem A, Owren PA. Adenosine diphosphate in red cells as a factor in the adhesiveness of human platelets. Nature 1961;192:531–532.

    Article  PubMed  CAS  Google Scholar 

  44. Haslam RJ, Cusack NJ. Blood platelet receptors for ADP and adenosine. Purinergic Receptors (Receptors and Recognition, Series B, Vol 12), In Burnstock G, editors. Chapman and Hall, London, 1981;223–278.

    Google Scholar 

  45. Mustard JF, Packham MA Factors influencing platelet function: adhesion, release and aggregation, Pharmacol Rev 1970;22:97–187.

    PubMed  CAS  Google Scholar 

  46. Mills DCB, Robb JA, Roberts GCK. The release of nucleotides, 5-hydroxytryptamine and enzymes from human platelet. J Physiol 1968;195:715–729.

    PubMed  CAS  Google Scholar 

  47. Haslam RJ. Mechanisms of platelet aggregation. Physiology of Hemostasis and Thrombosis. In Johnson SA, Seegers WH, editors. Charles C. Thomas, Springfield, IL, 1967;88–112.

    Google Scholar 

  48. Zucker MB, Peterson J. Inhibition of adenosine diphosphate-induced secondary aggregation and other platelet functions by acetylsalicylic acid ingestion. Proc Soc Exp Biol Med 1968;127:547–551.

    PubMed  CAS  Google Scholar 

  49. Packham MA. Mode of action of acetylsalicylic acid. Acetylsalicylic Acid — New Uses for an Old Drug. In Barnett HJM, Hirsh J, Mustard JF, editors. Raven Press, New York, NY, 1982;63–82.

    Google Scholar 

  50. Lasslo A, Quintana RP. Interaction dynamics of blood platelets with medicinal agents and other chemical entities. Blood Platelet Function and Medicinal Chemistry. Lasslo A, editor. Elsevier Biomedical, New York, NY, 1984;229–315.

    Google Scholar 

  51. Haslam RJ, Cusack NJ. Blood platelet receptors for ADP and adenosine. Purinergic Receptors. Burnstock G, editors. Chapman and Hill, London, 1981;223–285.

    Google Scholar 

  52. Mills DCB, Macfarlane DC. Platelet receptors. Platelets in Biology and Pathology. Gordon JL, editor. Elsevier/North Holland Biomedical Press, New York, NY, 1976;159–202.

    Google Scholar 

  53. Nachman RL, Ferris B. Binding of adenosine diphosphate by isolated membranes from human platelets. J Biol Chem 1974;249:704–710.

    PubMed  CAS  Google Scholar 

  54. Gough G, Maguire MH, Penglis F. Analogues of adenosine 5′- diphosphate: New platelet aggregators. Influence of purine ring and phosphate chain substitutions on the platelet-aggregating potency of adenosine 5′-diphosphate. Mol Pharmacol 1972;8:170–177.

    PubMed  CAS  Google Scholar 

  55. Bennett JS, Colman RF, Colman RW. Identification of adenine nucleotide binding proteins in human platelet membranes by affinity labeling with 5′-p-fluorosulfonylbenzoyl adenosine. J Biol Chem 1978;253:7346–7354.

    PubMed  CAS  Google Scholar 

  56. Colman RW. Aggregin: a platelet ADP receptor that mediates activation, FASEB J 1990;4:1425–1435.

    PubMed  CAS  Google Scholar 

  57. Ts’ao C. Rat platelet aggregation by ATP. Am J Pathol 1976;85:581–592.

    PubMed  Google Scholar 

  58. Haskel EJ, Agarwal KC, Parks RE Jr. ATP- and ADP-induced rat platelet aggregation: Significance of plasma in ATP-induced aggregation. Thromb Haemost 1979;42:1580–1588.

    Google Scholar 

  59. Martin W, Cusack NJ, Carleton JS, Gordon JL. Specificity of P 2 -purinoceptor that mediates endothelium-dependent relaxation of the pig aorta. Eur J Pharmacol 1985;108:295–299.

    Article  PubMed  CAS  Google Scholar 

  60. Burnstock G, Kennedy C. A dual function for ATP in the regulation of vascular tone. Circ Res 1986;58:319–330.

    PubMed  CAS  Google Scholar 

  61. Carter TD, Hallam TJ, Cusack NJ, Pearson JD. Regulation of P 2y -purinoceptor-mediated prostacyclin release from human endothelial cells by cytoplasmic calcium concentration. Br J Pharmacol 1988;95:1181–1190.

    PubMed  CAS  Google Scholar 

  62. Boeynaems JM, Pirotton S, Coevorden AV, Raspe E, Demolie D, Erneux C. P 2 -Purinergic receptors in vascular endothelial cells: From concept to reality. J Receptor Res 1988;8:121–132.

    CAS  Google Scholar 

  63. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 1962;194:927–929.

    Article  PubMed  CAS  Google Scholar 

  64. Mills DCB, Smith JB. The influence on platelet aggregation of drugs, Biochem J 1971;121:185–196.

    PubMed  CAS  Google Scholar 

  65. Agarwal KC, Huzoor-Akbar, Parks RE Jr. Vasopressin-induced intracellular calcium mobilization in human platelets: Blockade by adenosine. Thromb Haemost 1993;69:1243.

    Google Scholar 

  66. Stafford A. Potentiation of adenosine and adenine nucleotides by dipyridamole. Br J Pharmacol 1966;28:218–227.

    CAS  Google Scholar 

  67. Asano T, Ochiai Y, Hidaka H. Selective inhibition of separated forms of human platelet cyclic nucleotide phosphodiestease by platelet aggregation inhibitors. Mol Pharmacol 1977;13:400–406.

    PubMed  CAS  Google Scholar 

  68. Paterson ARP, Jakobs BS, Harley ER, Fu NU, Robins MJ, Cass CE. Inhibition of nucleoside transport. Regulatory Functions of Adenosine. In Berne RM, Rail TW, Rubio R, editors. Martinus Nijhoff Publishers, The Hague, 1983, 203–220.

    Google Scholar 

  69. El-Gamel S, Wollert U, Müller WE. Optical studies on the specific interaction of dipyridamole with alphas-acid glycoprotein (orosomucoid). J Pharm Pharmacol 1981;34:152–157.

    Article  Google Scholar 

  70. Klabunde RE. Dipyridamole inhibition of adenosine metabolism in human blood. Eur J Pharmacol 1983;93:21–26.

    Article  PubMed  CAS  Google Scholar 

  71. Sollevi A, Ostergren J, Fagrell B, Hjemdahl P. Theophylline antagonizes cardiovascular responses to dipyridamole in man without affecting increases in plasma adenosine. Acta Physiol Scand 1984;121:165–171.

    Article  PubMed  CAS  Google Scholar 

  72. Dawicki DD, Agarwal KC, Parks RE Jr. Potentiation of the antiplatelet action of adenosine in whole blood by dipyridamole or dilazep and the cAMP phosphodiesterase inhibitor, RA-233. Thromb Res 1986;43:161–175.

    Article  PubMed  CAS  Google Scholar 

  73. Gresele P, Arnout J, Deckmyn H, Vermylen J. Mechanism of the antiplatelet action of the dipyridamole in whole blood: Modulation of adenosine concentration and activity. Thomb Haemost 1986;55:12–18.

    CAS  Google Scholar 

  74. Takehara K, Igarashi A, Ishibashi Y. Dipyridamole specifically decreases platelet-derived growth factor release from platelets. Pharmacology 1990;40:150–156.

    Article  PubMed  CAS  Google Scholar 

  75. Lugnier C, Schoeffter P, Bee AL, Strouthou E, Stoclet JC. Selective inhibition cyclic nucleotide phosphodiesterases of human, bovine and rat aorta. Biochem Pharmacol 1986;35:1743–1751.

    Article  PubMed  CAS  Google Scholar 

  76. Bult H, Fret HRL, Jordaens FH, Herman AG. Dipyridamole potentiates platelet inhibition by nitric oxide. Thromb Haemost 1991;66:343–349.

    PubMed  CAS  Google Scholar 

  77. Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1982;1:129–132.

    Article  Google Scholar 

  78. Ukena D, Shamim MT, Padgett W, Daly JW. Analogs of caffeine: antagonists with selectivity for A 2 adenosine receptors. Life Sci 1986;39:743–750.

    Article  PubMed  CAS  Google Scholar 

  79. Biaggioni I, Paul S, Puckett A, Arzubiaga C. Caffeine and theophylline as adenosine receptor antagonists in humans. J Pharmacol Exp Ther 1991;258:588–593.

    PubMed  CAS  Google Scholar 

  80. Daly JW. Analogs of caffeine and theophylline: activity as antagonists at adenosine receptors. Role of Adenosine and Adenine Nucleotides in the Biological System. Imai S, Nakazawa M, editors. Elsevier Science BV, Amsterdam, 1991;119–129.

    Google Scholar 

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Agarwal, K.C. (1996). Purines and Regulation of Platelet Activation. In: Abd-Elfattah, AS.A., Wechsler, A.S. (eds) Purines and Myocardial Protection. Developments in Cardiovascular Medicine, vol 181. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-0455-5_25

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  • DOI: https://doi.org/10.1007/978-1-4613-0455-5_25

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