Mechanism of Action and Clinical Use of Prostanoids

  • Giovanni de Gaetano
  • Vittorio Bertelé
  • Chiara Cerletti


Aspirin reduces cardiovascular mortality most likely by suppressing platelet thromboxane A2 (T×A2) generation, despite a variable degree of inhibition of vascular prostacyclin (PGI2) production [1]. This implies that suppression of platelet activatory and vasoconstrictory prostanoids is clinically beneficial and that such a benefit is not hidden by the concomitant reduced availability of prostanoids provided with opposite biological effects, such as PGE1 and PGI2. However, the prominent role of T×A2 does not rule out the possibility thatpromotion of endogenous PGI2 production or administration of exogenous analogues may have a therapeutic effect in particular clinical situations.


Peripheral Artery Disease Ulcer Healing Rest Pain Ulcer Size Thromboangiitis Obliterans 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    de Gaetano G (1988) Primary prevention of vascular disease by aspirin. Lancet I:1093–1094CrossRefGoogle Scholar
  2. 2.
    Antiplatelet Trialists’ Collaboration (1988) Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 296:320–331CrossRefGoogle Scholar
  3. 3.
    Armstrong JM, Lattimer N, Moncada S, Vane JR (1978) Comparison of the vasodepressor effects of prostacyclin and 6-oxo-prostaglandin F with those of prostaglandin E2 in rats and rabbits. Br J Pharmacol 62:105–129Google Scholar
  4. 4.
    Waldhan HM, Alter I, Kot PA, Rose JC, Ramwell PW (1978) Effect of lung transit on systemic depressor responses to arachidonic acid and prostacyclin in dogs. J Pharmacol Exp Ther 204:289–293Google Scholar
  5. 5.
    Patrono C, Preston FE, Vermylen J (1984) Platelet and vascular arachidonic acid metabolites: can they help detect a tendency towards thrombosis? Br J Haematol 57:209–212PubMedGoogle Scholar
  6. 6.
    Higgs EA, Moneada S, Vane JR (1977) Effect of prostacyclin (PGI2) on platelet adhesion to rabbit arterial subendothelium. Prostaglandins 16:17–22CrossRefGoogle Scholar
  7. 7.
    Leytin VL, Sviridov DD (1982) A model for studying platelet interaction with cellular and macromolecular constituents of the vessel wall in vitro. In: Chazov EI, Smirnov VN (eds) Vessel wall in athero– and thrombo-genesis. Studies in USSR. Springer, Berlin Heidelberg New York, p 173Google Scholar
  8. 8.
    Ehrmann HL, Jaffe EA (1980) Prostacyclin (PGI2) inhibits the development in human platelets of ADP and arachidonic acid-induced shape change and pro-coagulant activity. Prostaglandins 20:1103–1116CrossRefGoogle Scholar
  9. 9.
    Moneada S, Gryglewski RJ, Bunting S, Vane JR (1976) An enzyme transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263:663–665CrossRefGoogle Scholar
  10. 10.
    Karniguaian A, Legrand JP, Caen JP (1982) Prostaglandins: specific inhibition of platelet adhesion to collagen and relationship with cAMP level. Prostaglandins 23:437–457CrossRefGoogle Scholar
  11. 11.
    Hawiger J, Parkinson S, Timmons S (1980) Prostacyclin inhibits mobilisation of fibrinogen– binding sites on human ADP and thrombin-treated platelets. Nature 283:195–198PubMedCrossRefGoogle Scholar
  12. 12.
    Pedvis LG, Wong T, Frojmovic MM (1988) Differential inhibition of the platelet activation sequence: shape change, micro– and macro-aggregation by a stable prostacyclin analogue (iloprost). Thromb Haemost 59:323–328PubMedGoogle Scholar
  13. 13.
    Sinzinger H, Silberbauer K, Horsch AK, Gall A (1981) Decreased sensitivity of human platelets to PGI2 during long term intraarterial prostacyclin infusion in patients with peripheral vascular disease. A rebound phenomen? Prostaglandins 21:49–51PubMedCrossRefGoogle Scholar
  14. 14.
    Yardumian DA, Mackie IJ, Brennan EC, Bull H, Machin SJ (1986) Platelet function studies during and after infusion of ZK 36374, a stable prostacyclin analogue, to healthy volunteers. Haemostasis 16:20–26PubMedGoogle Scholar
  15. 15.
    Bertelé V, Stemerman M, Shafer A, Adelman B, Smith M, Fuhro R, Salzman EW (1985) Refractoriness of platelets to prostaglandins after infusion in rabbits. J Lab Clin Med 106:551–561PubMedGoogle Scholar
  16. 16.
    Fitscha P, Tiso B, Krais T, Sinzinger H (1987) Effect of iloprost on in vivo and in vitro platelet function in patients with peripheral vascular disease. In: Samuelsson B, Paoletti R, Ramwell PW (eds) Adv Prostaglandin Thromboxane Leukotriene Res, vol 17. Raven Press, New York, pp 450–454Google Scholar
  17. 17.
    Modesti PA, Fortini A, Poggesi L, Boddi M, Abbate R, Gensini GF (1987) Acute reversible reduction of PGI2 platelet receptors after iloprost infusion in man. Thromb Res 48:663–669PubMedCrossRefGoogle Scholar
  18. 18.
    Darius H, Hossmann V, Schror (1986) Antiplatelet effect of intravenous iloprost in patients with peripheral arterial obliterative disease. Klin Wochenschr 64:545–551PubMedCrossRefGoogle Scholar
  19. 19.
    Sinzinger H, Fitscha P (1984) Epoprostenol and platelet deposition in atherosclerosis. Lancet I:905–906CrossRefGoogle Scholar
  20. 20.
    Turker RK, Demirel E (1988) Iloprost maintains acetylcholine relaxations of isolated rabbit aortic strips submitted to hypoxia. Pharmacology 36:151–155PubMedCrossRefGoogle Scholar
  21. 21.
    Belch JJF, Saniabaldi AR, Forbes CD (1987) Whole blood white cell aggregation: a novel technique. Thromb Res 48:631–639PubMedCrossRefGoogle Scholar
  22. 22.
    Del Maschio A, Evangelista V, Rajtar G, Chen ZM, Cerletti C, de Gaetano G (1990) Platelet activation by polymorphonuclear leukocytes exposed to chemotactic agents. Am J Physiol 258:H870-H879PubMedGoogle Scholar
  23. 23.
    Ernst E, Hammerschmidt DE, Bagge VU, Matrai A, Dormandy J A (1987) Leukocytes and the risk of ischemic disease. JAMA 257:2318–2324PubMedCrossRefGoogle Scholar
  24. 24.
    Simpson PJ, Lucchesi BR (1987) Free radicals and myocardial ischemia and reperfusion injury. J Lab Clin Med 110:13–30PubMedGoogle Scholar
  25. 25.
    Simpson PJ, Mickelson J, Fantone JC, Gallagher KP, Lucchesi BR (1987) Iloprost inhibits neutrophil function in vitro and in vivo and limits experimental infarct size in canine heart. Circ Res 60:666–673PubMedGoogle Scholar
  26. 26.
    Ham EA, Soderman DD, Zanetti ME, Dougherty HW, McCauley E, Kuehl F (1983) Inhibition by prostaglandins of leukotriene B4 release from activated neutrophils. Proc Natl Acad Sci USA 80:4349–4353PubMedCrossRefGoogle Scholar
  27. 27.
    Smith RJ, Iden SS (1980) Pharmacological modulation of chemotactic factor-elicited release of granule-associated enzymes from human neutrophils. Biochem Pharmacol 29:2389–2395PubMedCrossRefGoogle Scholar
  28. 28.
    Fantone JC, Kunkel SL, Ward PA, Zurier RB (1981) Suppression of human polymorphonuclear leukocyte function after intravenous infusion of PGE1. Prostaglandins Leukotrienes Med 2:195Google Scholar
  29. 29.
    Fantone JC, Kinnes DA (1983) Prostaglandin E1 and prostaglandin I2 modulation of superoxide production by human neutrophils. Biochem Biophys Res Commun 113:506–512PubMedCrossRefGoogle Scholar
  30. 30.
    Melin J A, Becker LC (1983) Salvage of ischemic myocardium by prostacyclin during experimental myocardial infarction. J Am Coll Cardiol 2:279–286PubMedCrossRefGoogle Scholar
  31. 31.
    Chiariello M, Golino P, Cappelli-Bagazzi M, Ambrosio G, Tritto I, Salvatore M (1988) Reduction in infarct size by the prostacyclin analogue iloprost (ZK 36374) after experimental coronary artery occlusion reperfusion. Am Heart J115:499–504CrossRefGoogle Scholar
  32. 32.
    Ferrari R, Cargnoni A, Ceconi C, Curello S, Belloli S, Albertini A, Visioli O (1988) Protective effect of a prostacyclin-mimetic on the ischaemic-reperfused rabbit myocardium. J Mol Cell Cardiol 20:1095–1106PubMedCrossRefGoogle Scholar
  33. 33.
    Lefer AM, Ogletree MNL, Smith JB, Silver MJ, Nicolaou KC, Barnette WE, Gasic GP (1978) Prostacyclin: a potentially valuable agent for preserving ischemic myocardial tissue in acute myocardial ischemia. Science 200:52–54PubMedCrossRefGoogle Scholar
  34. 34.
    Jugdutt BI, Hutchins GM, Bulkley BH, Becker LC (1981) Dissimilar effects of prostacyclin, prostaglandin E1 and prostaglandin E2 on myocardial infarct size after coronary occlusion in conscious dogs. Circ Res 49:685–700PubMedGoogle Scholar
  35. 35.
    Schrör K, Addicks K, Darius H, Ohlendorf R, Rösen P (1981) PGI2 inhibits ischemia- induced platelet activation and prevents myocardial damage by inhibition of catecholamine release. Evidence for cAMP as a common denominator. Thromb Res 21:175–180Google Scholar
  36. 36.
    Schrör K, Funke K (1985) Prostaglandins and myocardial noradrenaline overflow after sympathetic nerve stimulation during ischemia and reperfusion. J Cardiovasc Pharmacol 7, (suppl 5):S50-S54PubMedCrossRefGoogle Scholar
  37. 37.
    Dembinska-Kiec A, Kostka-Trabka E, Gryglewski RJ (1982) Effect of prostacyclin on fibrinolytic activity in patients with arteriosclerosis obliterans. Thromb Haemostas 47:190Google Scholar
  38. 38.
    Szczeklik A, Kopec M, Sladek K, Musial J, Chmielewska J, Teisseyre E, Dudek– Wojciechowska G, Palester-Chlebowczyk M (1983) Prostacyclin and the fibrinolytic system in ischemic vascular disease. Thromb Res 29:655–660PubMedCrossRefGoogle Scholar
  39. 39.
    Musial J, Wilczynska M, Sladek K, Cierniewski CS, Nizankowski R, Szczeklik A (1986) Fibrinolytic activity of prostacyclin and iloprost in patients with peripheral arterial disease. Prostaglandins 31:61–70PubMedCrossRefGoogle Scholar
  40. 40.
    de Gaetano G, Carriero MR, Cerletti C, Mussoni L (1986) Low dose aspirin does not prevent fibrinolytic response to venous occlusion. Biochem Pharmacol 35:3147–3150PubMedCrossRefGoogle Scholar
  41. 41.
    Bertelé V, Mussoni L, Del Rosso G, Pintucci G, Carriero MR, Merati MG, Libretti A, de Gaetano G (1988) Defective fibrinolytic response in atherosclerotic patients. Effect of iloprost and its possible mechanism of action. Thromb Haemost 60:141–144PubMedGoogle Scholar
  42. 42.
    Bertelé V, Mussoni L, Pintucci G, Del Rosso G, Romano G, de Gaetano G, Libretti A (1989) The inhibitory effect of aspirin on fibrinolysis is reversed by iloprost, a prostacyclin analogue. Thromb Hemost 61:286–288Google Scholar
  43. 43.
    Roberts DH, Linge K, Nixon DP, Chatlani PT, Mc Loughlin GA, Breckenridge AM (1988) The effect of iloprost on calf blood flow in patients with severe peripheral arterial disease. Br J Clin Pharmacol 25:147–148Google Scholar
  44. 44.
    Roberts DH, Linge K, Nixon DP, Chatlani PT, Mc Loughlin GA, Breckenridge AM (1988) The effect of iloprost on calf blood flow in patients with stable intermittent claudication. Br J Clin Pharmacol 25:148–149Google Scholar
  45. 45.
    Ernst E, Marshall M, Matrai A (1988) Does prostacyclin analogue iloprost change blood rheology? Vasa 17:89–91PubMedGoogle Scholar
  46. 46.
    Robert A (1976) Antisecretory, antiulcer, cytoprotective and diarrheogenie properties of prostaglandins. In: Samuelsson B, Paoletti R (eds) Adv Prostaglandins Thromboxane Res 2:507–520Google Scholar
  47. 47.
    Hajrjar DP, Weksler BB (1983) Metabolic activity of cholesteryl esters in aortic smooth muscle cells is altered by prostaglandins I2 and E2. J Lipid Res 24:1176–1185Google Scholar
  48. 48.
    Orekhov AN, Tertov W, Mazurov AV, Andreeva ER, Repin VS, Smirnov VN (1986) “Regression” of atherosclerosis in cell culture: effects of stable prostacyclin analogues. Drug Dev Res 9:189–201CrossRefGoogle Scholar
  49. 49.
    Willis AL, Smith DL, Vigo C, Kluge AF (1986) Effects of prostacyclin and orally active stable mimetic agent RS-93427–007 on basic mechanism of atherogenesis. Lancet II:682–683CrossRefGoogle Scholar
  50. 50.
    Orekhov AN, Tertov W, Smirnov VN (1983) Prostacyclin analogues as anti– atherosclerotie drugs. Lancet II:521CrossRefGoogle Scholar
  51. 51.
    Carlson LA, Eriksson I (1973) Femoral-artery infusion of prostaglandin E1 in severe peripheral vascular disease. Lancet I:155–156CrossRefGoogle Scholar
  52. 52.
    Carlson LA, Olsson AG (1976) Intravenous prostaglandin in severe peripheral vascular disease. Lancet II:810CrossRefGoogle Scholar
  53. 53.
    Sethi GK, Scott SM, Takaro T (1980) Effect on intra-arterial infusion of PGE1 in patients with severe ischemia of lower extremity. J Cardiovasc Surg 21:185–191Google Scholar
  54. 54.
    Grass JD, Bartels D, Ohta T, Machado JL, Schlechtweg B (1982) Conservative treatment of inoperable arterial occlusions of the lower extremities with intra-arterial prostaglandin E1 Br J Surg 69:S11-S13CrossRefGoogle Scholar
  55. 55.
    Cronenwett JL (1986) The use of prostaglandins PGE1 and PGI2 in peripheral arterial ischemia. J Vase Surg 3:370–374Google Scholar
  56. 56.
    Sakaguchi S, Kusaba A, Mishima Y, Kamya K, Nishimura A, Furukawa K, Shionoya S, Kawashima M, Katsumura T, Sakuma A (1978) A multi-clinical double blind study with PGEi (α-cyclodextrin clathrate) in patients with ischemic ulcer of the extremities. Vasa 7:263–267PubMedGoogle Scholar
  57. 57.
    Böhme H, Brülisauer M, Härtel U, Bollinger A (1987) Kontrollierte Studie zur Wirksamkeit von i.a. Prostaglandin E1 Infusionen bei peripherer arterieller Verschlußkrankheit im Stadium III und IV. Vasa (Suppl 20):206–208Google Scholar
  58. 58.
    Trübestein G, Diehm C, Gruss JD, Horsch S (1987) Prostaglandin E1 in chronic arterial disease-a multicenter study. Vasa (Suppl 17):39–43Google Scholar
  59. 59.
    Eklund AE, Eriksson G, Olsson AG (1982) A controlled study showing significant short term effect of prostaglandin E1 in healing of ischaemic ulcers of the lower limb in man. Prostaglandins Leukotrienes Med 8:265–271CrossRefGoogle Scholar
  60. 60.
    Schuler JJ, Flanigan DP, Holcroft JW, Ursprung JJ, Mohrland JS, Pyke J (1984) Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease. J Vase Surg 1:160–170Google Scholar
  61. 61.
    Rhodes RS, Heard SE (1983) Detrimental effect of high-dose prostaglandin E1 in the treatment of ischemic ulcers. Surgery 93:839–842PubMedGoogle Scholar
  62. 62.
    Teiles GS, Campbell WB, Wood RFM, Collin J, Baird RN, Morris PJ (1984) Prostaglandin Ej in severe lower limb ischaemia: a double-blind controlled trial. Br J Surg 71:506–508CrossRefGoogle Scholar
  63. 63.
    Jogestrand T, Olsson AG (1985) The effect of intravenous prostaglandin E1 on ischaemic pain and on leg blood-flow in subjects with peripheral artery disease: a double-blind controlled study. Clin Physiol 5:495–502PubMedCrossRefGoogle Scholar
  64. 64.
    Diehm C, Stammler F, Hübsch-Müller C, Eckstein HH, Simini B (1987) Clinical effects of intravenously administered prostaglandin E1 in patients with rest pain due to peripheral obliterative arterial disease (POAD). A preliminary report on a placebo-controlled double- blind study. Vasa (Suppl 17):52–56Google Scholar
  65. 65.
    Szczeklik A, Skawinski S, Gluszko P, Nizankowski R, Szczeklik J, Gryglewski RJ (1979) Successful therapy of advanced arteriosclerosis obliterans with prostacyclin. Lancet I:1111–1114CrossRefGoogle Scholar
  66. 66.
    Szczeklik A, Gryglewski RJ (1982) Prostaglandins as therapeutic agents in cardiovascular disease. In: Herman AG, Vanhoutte PM, Denolin H, Goossens A (eds) Cardiovascular pharmacology of the prostaglandins. Raven Press, New York, pp 347–359Google Scholar
  67. 67.
    Pardy BJ, Lewis JD, Eastcott HHG (1981) Preliminary experience with prostaglandin E1 and I2 in peripheral vascular disease. Surgery 88:826–832Google Scholar
  68. 68.
    Vermylen J, Chamone DAF, Machin SJ, Defreyn CR, Verstraete M (1980) Prostacyclin in inoperable ischaemic rest pain. Acta Ther 6:33Google Scholar
  69. 69.
    Belch JJF, McKay A, McArdle BM, Leiberman P, Pollock JG, Lowe GDO, Forbes CD, Prentice CRM (1983) Epoprostenol (prostacyclin) and severe arterial-disease. A double– blind trial. Lancet I:315–317CrossRefGoogle Scholar
  70. 70.
    Hossmann V, Auel H, Rücker W, Schrör K (1984) Prolonged infusion of prostacyclin in patients with advanced stages of peripheral vascular disease: a placebo-controlled crossover study. Klin Wochenschr 62:1108–1114PubMedCrossRefGoogle Scholar
  71. 71.
    Cronenwett JL, Zelenock GB, Whitehouse WM, Lindenauer SM, Graham LM, Stanley JC (1986) Prostacyclin treatment of ischemic ulcers and rest pain in unrecontructible peripheral arterial occlusive disease. Surgery 100:369–375PubMedGoogle Scholar
  72. 72.
    Karnik R, Valentin A, Slany J (1987) Prostacyclin versus naftidrofuryl. Herz/Kreislauf 1:23–26Google Scholar
  73. 73.
    Nizankowski R, Krolikowski W, Beilatowicz J, Szczeklik A (1985) Prostacyclin for ischemic ulcers in peripheral arterial disease. A random-assignement, placebo-controlled study. Thromb Res 37:21–28Google Scholar
  74. 74.
    Negus D, Irving JD, Friedgood A (1987) Intra-arterial prostacyclin compared to praxilene in the management of severe lower limb ischaemia: a double-blind trial. J Cardiovasc Surg 28:196–199Google Scholar
  75. 75.
    Chiesa R, Vicari A, Mari G, Galimberti M, Di Carlo V, Pozza G (1985) Use of stable prostacyclin analogue ZK36374 to treat severe lower limb ischaemia. Lancet II:95–96CrossRefGoogle Scholar
  76. 76.
    Hossmann V, Auel H, Schrör K (1984) Placebo kontrollierte Cross-Over-Studie über die Wirkung von Iloprost (ZK 36 374) auf fortgeschrittene Stadien der arteriellen Verschlußkrankheit. In: Trübstein G (ed) Konservative Therapie arterieller Durchblutungsstörungen. Bonn, pp 186–191Google Scholar
  77. 77.
    Oberender H, Krais Th, Schäfer M, Belcher G (1989) Clinical benefits of iloprost, a stable prostacyclin (PGI2) analog, in severe peripheral arterial disease (PAD). In: Samuelsson B, Wong YK (eds) Adv Prostaglandin Thromboxane Leukotriene Res 19:311–316Google Scholar
  78. 78.
    Diehm C, Abri O, Baitsch G et al. (1989) Iloprost, ein stabiles Prostacyclinderivat bei arterieller Verschlußkrankheit im Stadium IV. Dtsch Med Wochenschr 114:783–788PubMedCrossRefGoogle Scholar
  79. 79.
    Brock FE (1986) Placebo-controlled, double-blind multicenter study to determine the efficacy of PGI2-analogue, iloprost, in diabetics with ulcer and gangrene. 14th World Congress International Union of Angiology, München (abstract)Google Scholar
  80. 80.
    Balzer K, Bechara G, Bisler H, Clevert HD, Diehm C, Heisig G, Held K, Mahofoud Y, Mörl H, Rücker G, Stöveken HJ, Walter P, Wolf S (1987) Placebo-kontrollierte, doppelblinde Multicenterstudie zur Wirksamkeit von Iloprost bei der Behandlung ischämischer Ruheschmerzen von Patienten mit peripheren arteriellen Durchblutungsstörungen. Vasa (Suppl 20):379–381Google Scholar
  81. 81.
    European Consensus on critical limb ischemia (1989) Lancet I:737–738Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • Giovanni de Gaetano
  • Vittorio Bertelé
  • Chiara Cerletti

There are no affiliations available

Personalised recommendations