Advertisement

Pharmacological Interference in Arachidonic Acid Cascade

  • Ryszard J. Gryglewski
Part of the NATO Advanced Study Institutes Series book series

Abstract

In order to be metabolized by oxidative tissue enzymes arachidonic acid (AA) has to be liberated from the cellular phospholipids by phospholipase A2 (1). In certain cells, e.g. in platelets, phospholipase requires calcium ions for its optimal biochemical activity (2), and therefore Ca2+ ionophors activate AA cascade (3) while the drugs which rise intracellular cAMP levels sequestrate Ca2+, and thus inhibit AA liberation and its subsequent metabolism (4). Mepacrine and bromophenacetyl bromide are direct inhibitors of phospholipase A2 (5). We have proposed (6,7) that the liberation of AA from intact tissues is hindered by glucocorticosteroids as well as by anti-inflammatory steroids, eg. dexymethasone. Other authors since have confirmed our hypothesis (8,9,10), and Flower and Blackwell (11) demonstrated that glucocorticosteroids induce the endogenous synthesis of a phospholipase A2 inhibitor.

Keywords

Platelet Aggregation Human Platelet Dienoic Acid Prostaglandin Biosynthesis Arachidonic Acid Cascade 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    G. J. Blackwell, W. G. Duncombe, R. J. Flower, M. F. Parsons, and J. R. Vane, The distribution and metabolism of arachidonic acid in rabbit platelets during aggregation and its modification by drugs. Br. J. Pharmacol., 59: 353 (1977).PubMedCrossRefGoogle Scholar
  2. 2.
    A. Derksen and P. Cohen, Patterns of fatty acid release from endogenous substrates by human platelet homogenates and membranes. J. Biol. Chem., 250: 9342 (1975).PubMedGoogle Scholar
  3. 3.
    W. C. Pickett, R. L. Jesse and P. Cohen, Initiation of phospholipase A22 activity in human platelets by the calcium ion ionophore A23187. Biochem. Biophys. Acta., 486: 209 (1977).CrossRefGoogle Scholar
  4. 4.
    J. G. White, J. M. Gerrard, Platelet morphology and the ultra-structure of regulatory mechanisms involved in platelet activation. In:”Platelets: A Multidisciplinary Approach”. G. de Gaetano and S. Garattini,eds., Raven Press, New York (1978).Google Scholar
  5. 5.
    B.B.Vargaftig, Carrageenan and thrombin trigger prostaglandin synthetase-independent aggregation of rabbit platelets: inhibition by phospholipase A2 inhibitors. J. Pharm. Pharmac. 29: 222 (1977).CrossRefGoogle Scholar
  6. 6.
    R. J. Gryglewski, B. Panczenko,. R. Korbut, L. Grodzinska and A. Ocetkiewicz, Corticosteroids inhibit prostaglandin release from perfused lungs of sensitized guinea pigs. Prostaglandins, 10: 343 (1975).PubMedGoogle Scholar
  7. 7.
    R. J. Gryglewski, Steroid hormones, anti-inflammatory steroids and prostaglandins. Pharmacol. Res. Commun., 8: 337 (1976).PubMedCrossRefGoogle Scholar
  8. 8.
    R. J. Flower, Steroidal anti-inflammatory drugs as inhibitors of phospholipase A2. In: “Advances in Prostaglandin and Thramboxane Research”. C. Galli, G. Galli and G. Porcellati, eds., Vol. 3, Raven Press, New York (1978).Google Scholar
  9. 9.
    Y. Floman, N. Floman and U. Zor, Inhibition of prostaglandin E. release by anti-inflammatory steroids. Prostaglandins, 11: 591 (1976).Google Scholar
  10. 10.
    F. P. Nijkamp, R. J. Flower, S. Moncada and J. R. Vane, Partial purification of rabbit aorta contracting substance-releasing factor and inhibition of its activity by anti-inflammatory steroids. Nature (London), 263: 479 (1976).Google Scholar
  11. 11.
    R. J. Flower and G. J. Blackwell, Anti-inflammatory steroids induce the biosynthesis of a phospholipase A2 inhibitor which prevents prostaglandin generation. Nature, 278: 456 (1979).PubMedCrossRefGoogle Scholar
  12. 12.
    B. Samue1sson, P. Borgeat, S. Hammarström and R. C. Murphy, Introduction of a nomenclature: Leukotriens: In: “Abstracts of International Conference on Prostaglandins,” Washington D.C. 28th May, 1979.Google Scholar
  13. 13.
    R. J. Flower, Drugs which inhibit prostaglandin biosynthesis. Pharmacol. Rev., 26: 33 (1974).PubMedGoogle Scholar
  14. 14.
    J. R. Vane, Inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs. Nature New Biol. 231: 232 (1971).PubMedGoogle Scholar
  15. 15.
    J. B. Smith and A. L. Willis, Aspirin selectively inhibits prostaglandin production in human platelets. Nature New Biol., 231: 235 (1971).PubMedGoogle Scholar
  16. 16.
    S. H. Ferreira, S. Moncada and J. R. Vane, Indomethacin and aspirin abolish prostaglandin release from the spleen. Nature New Biol., 231: 237 (1971).PubMedCrossRefGoogle Scholar
  17. 17.
    R. J. Flower, R. J. Gryglewski, K. Herbaczynska-Cedro and J. R. Vane, The effect of anti-inflammatory drugs on prostaglandin biosynthesis. Nature New Biol, 238: 104 (1972).PubMedGoogle Scholar
  18. 18.
    F. A. Kuehl, J. L. Humes, R. W. Egan, E. A.Ham, G. C. Beveridge and C. G. Van Arman, Role of prostaglandin endoperoxide PGG2 in inflammatory processes. Nature, 265: 170 (1977).PubMedCrossRefGoogle Scholar
  19. 19.
    P. Krupp and M. Wesp, Inhibition of prostaglandin synthetase by psychotropic drugs. Experientia (Basel) 31: 330 (1975).CrossRefGoogle Scholar
  20. 20.
    R. E. Lee, The influence of psychotropic drugs on prostaglandin biosynthesis. Prostaglandins, 5: 63 (1974).PubMedGoogle Scholar
  21. 21.
    M. Hallberg and B. B. Fredholm, Isomerization of prostaglandin H2 into prostaglandin D2 in the presence of serum albumin. Biochem. Biophys. Acta, 431: 189 (1976).CrossRefGoogle Scholar
  22. 22.
    P. Needleman, M. Minkes and A. Raz, Thromboxanes: selective biosynthesis and distinct biological properties. Science 193: 163 (1976).PubMedCrossRefGoogle Scholar
  23. 23.
    R. R. Gorman, Modulation of human platelet function by prostacyclin and thromboxane A2. Federation Proc., 38: 83 (1979).Google Scholar
  24. 24.
    J. Dyeberg, H. O. Bang, E. Stoffersen and J. R. Vane, Eicosapentanoic acid and prevention of thrombosis and atherosclerosis? Lancet, 2: 117 (1978).CrossRefGoogle Scholar
  25. 25.
    S. Morooka, M. Kobayaski and T. Shimamoto, Experimental ischemic heart disease induced by thromboxane A2 in rabbits. Jap. Circ. J. 41: 1373 (1977).PubMedCrossRefGoogle Scholar
  26. 26.
    M. D. Schneider and B. J. Kelman, A proposed mechanism/s of transitory ischemic injury to myocardium. Am. J. Vet. Res. 40: 170 (1979).PubMedGoogle Scholar
  27. 27.
    A. Szczeklik, R. Nizankowski, S. Skawinski, J. Szczeklik, P. Gluszko and R. J. Gryglewski, Successful therapy of advanced arteriosclerosis obliterans with prostacyclin. Lancet, 1: 1111 (1979).PubMedCrossRefGoogle Scholar
  28. 28.
    U. Diczfalusy and S. Hammarström, Inhibitors or thromboxane synthase in human platelets. Febs Letters, 82: 107 (1977).CrossRefGoogle Scholar
  29. 29.
    P. Needleman, B. Bryan, A. Wyche, S. D. Bronson, K. Eakins, J. A. Ferendelli and M. Minkes, Thromboxane synthetase inhibitors as pharmacological tools: differential biochemical and biological effects on platelet suspensions. Prostaglandins, 14: 897 (1977).PubMedGoogle Scholar
  30. 30.
    H-H Tai and B. Yuan, Studies on the thromboxane synthetizing system in human plat let microsomes. Biochim. Biophys. Acta., 531: 286 (1978).PubMedCrossRefGoogle Scholar
  31. 31.
    S. Moncada, P. Needleman, S. Bunting and J. R. Vane, Prostaglandin endoperoxide and thromboxane generating systems and their selective inhibition. Prostaglandins, 12: 323 (1976)PubMedGoogle Scholar
  32. 32.
    R. J. Gryglewski, A. Zmuda, R. Korbut, E. Krecioch and K. Bieron, Selective inhibition of thromboxane A2 biosynthesis in blood platelets. Nature, 267: 627 (1977).PubMedCrossRefGoogle Scholar
  33. 33.
    R. J. Gryglewski, R. Korbut, A. Ocetkiewicz and J. Stachura, In vivo method for quantitation of antiplatelet potency of drugs. Naunyn-Schmiedeberg’s Arch. Pharmacol., 302:25 (1978).CrossRefGoogle Scholar
  34. 34.
    S. Moncada, S. Bunting, K. Mullane, P. Thorogood, and J. R. Vane, Imidazole: a selective inhibitor of thromboxane synthetase. Prostaglandins, 13: 611 (1977).PubMedGoogle Scholar
  35. 35.
    H-H Tai and B. Yuan, On the inhibitory potency of imidazole and its derivatives on thromboxane synthetase. Biochem. Biophys. Res. Comm., 80: 236 (1978).PubMedCrossRefGoogle Scholar
  36. 36.
    G. Allan, K. Eakins, Burimamide is a selective inhibitor of thromboxane A2 biosynthesis in human platelet microsomes. Prostaglandins, 15: 659 (1978).PubMedGoogle Scholar
  37. 37.
    F. A. Fitzpatrick and R. R. Gorman, A comparison of imidazole and 9,11-azaprosta-5,13-dienoic acid - two selective thromboxane synthetase inhibitors,. Biochim. Biophys. Acta., 539: 162 (1978).PubMedCrossRefGoogle Scholar
  38. 38.
    K. E. Eakins, V. Rajadhyaksha and R. Schroer, Prostaglandin antagonism by sodium p-benzyl-4-(1-oxo-2-(-4-chlorobenzyl)-3-phenyl propyl) phenyl phosphonate (N-0164). Br.J. Pharmacol., 58: 333 (1976).PubMedCrossRefGoogle Scholar
  39. 39.
    B. J. R. Whittle, S. Moncada and J.R. Vane, Formation of prostacyclin by the gastric mucosa and its actions on gastric function. Prostaglandins, 15: 704 (1978).Google Scholar
  40. 40.
    K. E. Eakins and P. S. Kulkarni, Selective inhibitory actions of sodium p-benzyl-4-(1-oxo-2-(4-chlorobenzyl)-3-phenyl propyl) phenyl phosphate (N-0164) and indomethacin on the biosynthesis of prostaglandins and thromboxanes from arachidonic acid. Br. J. Pharmacol., 60: 135 (1977).PubMedCrossRefGoogle Scholar
  41. 41.
    J. E. Vincent and F. J. Zijlstra, Nicotinic acid inhibits thromboxane synthesis in platelets. Prostaglandins, 15: 629 (1978).PubMedGoogle Scholar
  42. 42.
    A. N. Makheja, J. Y. Vanderhoek and J. M. Bailey, Properties of inhibitor of platelet aggregation and thromboxane synthesis isolated from onion and garlic. Thrombosis. Haemostas., 42: 74 (1979).Google Scholar
  43. 43.
    P. H. Chanch, I. Sokan, A. P. H. Chanch and P. Clavel, A comparative study of anti-thromboxane synthetase activity of the microsomes from different parts of the bovine heart. Abstracts of the IVth International Prostaglandin Conference in Washington, D.C. May 27–31 1979.Google Scholar
  44. 44.
    E. J. Corey, K. C. Nicolaou, Y. Machida, C. Malmsten and B. Samuelsson, Synthesis and biological properties of a 9,11-azaprostanoid; highly active biochemical mimic of prostaglandin endoperoxides. Proc. Natl. Acad. Sci. USA., 72: 335 (1975).CrossRefGoogle Scholar
  45. 45.
    F. F. Sun, Biosynthesis of thromboxanes in human platelets. I. Characterization and assay of thromboxane synthetase. Biochem. Biophys. Res. Comm., 74: 1432 (1977).PubMedCrossRefGoogle Scholar
  46. 46.
    J. F. Charo, R. D. Feinman, T. C. Detwills, J. Smith, C. M. Ingerman and M. J. Silver, Prostaglandin endoperoxides and thromboxane A2 can induce platelet aggregation in the absence of secretion. Nature, 269: 66 (1977).PubMedCrossRefGoogle Scholar
  47. 47.
    G. L. Bundy and D. C. Peterson, The synthesis of 15-deoxy-9–11-epoxyimino prostaglandins potent thromboxane synthetase inhibitors. Tetrahedron Letters, 1: 41 (1978).CrossRefGoogle Scholar
  48. 48.
    R. R. Gorman, G. L. Bundy, D. C. Peterson, F. F. Sun, O. V. Miller and F. A. Fitzpatrick, Inhibition of human platelet thromboxane synthetase by 9,11-azaprosta-5,13-dienoic acid. Proc. Natl. Acad. Sci. USA, 74: 4007 (1977).PubMedCrossRefGoogle Scholar
  49. 49.
    R. R. Gorman, F. A. Fitzpatrick and O. V. Miller, A selective thromboxane synthetase inhibitor blocks the cAMP lowering activity of PGH2. Biochem. Biophys. Res. Commun., 79: 305 (1977).CrossRefGoogle Scholar
  50. 50.
    F. A. Fitzpatrick, G. L. Bundy, R. R. Gorman and T. Honohan, 9,11-Epoxyiminoprosta-5,13-dienoic acid is thromboxane A2 antagonist in human platelets. Nature, in press.Google Scholar
  51. 51.
    R. J. Gryglewski, S. Bunting, S. Moncada, R. J. Flower and J. R. Vane, Arterial walls are protected against deposition of platelet thrombi by a substance (Prostaglandin X) which they make from prostaglandin endoperoxides. Prostaglandins 12: 685 (1976).PubMedGoogle Scholar
  52. 52.
    J. A. Salmon, D. R. Smith, R. J. Flower, S. Moncada and J. R. Vane, Further studies on the enzymatic conversion of prostaglandin endoperoxide into prostacyclin by porcine aorta microsomes. Biochim. Biophys. Acta, 523: 250 (1978).PubMedCrossRefGoogle Scholar
  53. 53.
    W. I. Rosenblum and F. El-Sabban, Enhancement of platelet aggregation by tranylcypromine in mouse cerebal micro-vessels. Circulat. Res., 43: 238 (1978).PubMedCrossRefGoogle Scholar
  54. 54.
    A. Wennmalm, Effects of nicotine on cardiac prostaglandin and platelet thromboxane synthesis. Br. J. Pharmac., 64: 559 (1978).CrossRefGoogle Scholar
  55. 55.
    F. P. Nijkamp, S. Moncada, H. L. White and J. R. Vane, Diversion of prostaglandin endoperoxide metabolism by selective inhibition of thromboxane A2 biosynthesis in lung, spleen or platelets. Eur. J. Pharmacol., 44: 179 (1977).PubMedCrossRefGoogle Scholar
  56. 56.
    F. ten Hoor and J. F. A. Quadt, Effect of nicotine on prostacyclin production by the isolated pulsatingly perfused rat aorta. Abstracts of IVth International Prostaglandin Conference in Washington, D.C. May 28–31, 1979.Google Scholar

Copyright information

© Plenum Press, New York 1981

Authors and Affiliations

  • Ryszard J. Gryglewski
    • 1
  1. 1.Department of PharmacologyCopernicus Academy of Medicine in CracowCracowPoland

Personalised recommendations