Leukotrienes in the Lung and Cardiovascular System

  • Priscilla J. Piper
  • Marwa N. Samhoun
  • Dolores M. Conroy
  • H. B. Yaacob
  • N. C. Barnes
  • Jane M. Evans
  • J. F. Costello
Conference paper
Part of the NATO ASI Series book series (NSSA, volume 177)


The formation of leukotrienes (LTs) from arachidonic acid derived from phospholipids of the cell membrane is initially catalysed by 5-lipoxygenasel. Metabolism of the unstable epoxide LTA4 leads to the formation of LTB4 and the cysteinyl-containing LTs C4, D4 and E4. All these LTs have potent, although different, biological activities. LTB4 is a powerful chemotactic agent for leukocytes whereas LTs C4, D4 and E4 have potent smooth muscle stimulating actions and account for the biological activity of the allergic mediator previously known as slow-reacting substance of anaphylaxis (SRS-A)2. Leukotriene B4 has pro-inflammatory actions but little smooth muscle stimulating activity of its own whereas cysteinyl-containing LTs have potent actions in the cardiovascular system and in the airways in vitro and in vivo (see3,4).


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  1. 1.
    Samuelsson, B. 1983. Leukotrienes: a new class of mediators of immediate hypersensitivity reactions and inflammation. Adv. Prostaglandin,Thromboxane, Leukotriene Res. 11: 1–13.Google Scholar
  2. 2.
    Brocklehurst, W.E. 1960. The release of histamine and formation of a slow-reacting substance (SRS-A) during anaphylactic shock. J. Physiol. 151: 416–435.CrossRefGoogle Scholar
  3. 3.
    Piper, P.J. 1984. Formation and actions of leukotrienes. Phys. Rev. 64: 744–761.Google Scholar
  4. 4.
    Piper, P.J., and M.N. Samhoun. 1987. Leukotrienes. Brit. Med. Bull. 43 (2): 297–311.CrossRefGoogle Scholar
  5. 5.
    Dahlen, S-E., G. Hansson, P. Hedqvist, T. Bjorck, E. Granstrom, and B. Dahlen. 1983. Allergen challenge of lung tissue from asthmatics elicits bronchial contraction that correlates with the release of leukotrienes C4, D4 and E4. Proc. Natl. Acad. Sci. USA 80: 1712–1716.CrossRefGoogle Scholar
  6. 6.
    Barnett, K., and P.J. Piper. 1985. The release of leukotrienes from large and small airways of guinea-pig and man. Br. J. Pharmacol. 86: 642P. (Abstract)Google Scholar
  7. 7.
    Piper, P.J., L.G. Letts, and S.A. Galton. 1983. Generation of a leukotriene-like substance from porcine vascular and other tissues. Prostaglandins 25: 591–599.CrossRefGoogle Scholar
  8. 8.
    Piper, P.J., M.N. Samhoun, D.M. Conroy, N.C. Barnes, J.M. Evans and J.F. Costello. 1988. Leukotrienes and human airways. Adv. Prostaglandin, Thromboxane, Leukotriene Res. (In Press)Google Scholar
  9. 9.
    Piper, P.J., and S. Levene. 1987. Human umbilical arteries and veins: Generation of leukotrienes and responses to exogenous leukotrienes. Biol. Neonate 52: 9–15.CrossRefGoogle Scholar
  10. 10.
    Piper, P.J., J.W. Antoniw, and A.W.B. Stanton. 1988. Release of leukotrienes from porcine and human blood vessels by immunological and non-immunological stimuli. Ann. NY Acad. Sci. 524: 133–141.CrossRefGoogle Scholar
  11. 11.
    Krell, R.D., B.S. Tsai, A. Berdoulay, M. Barone, and R.E. Giles. 1983. Heterogeneity of leukotriene receptors in guinea-pig trachea. Prostaglandins 25: 171–178.CrossRefGoogle Scholar
  12. 12.
    Buckner, C.K., R.D. Krell, R.B. Laravuso, D.B. Coursin, P.R. Bernstein, and J.A. Will. 1986. Pharmacological evidence that human intralobar airways do not contain different receptors that mediate contractions to leukotriene C4 and leukotriene D4. J. Pharmacol. Exp. Tiler. 237: 558–562.Google Scholar
  13. 13.
    Samhoun, M.N., and P.J. Piper. 1984. Leukotriene F4: Comparison of its pharmacological profile with that of the other cysteinyl-containing leukotrienes in guinea-pig ileum and lung parenchyma in vitro. Prostaglandins 28: 623–628.CrossRefGoogle Scholar
  14. 14.
    Bernström, K., and S. Hammarström. 1986. Metabolism of leukotriene E4 by rat tissues: formation of N-Acetyl leukotriene E4. Arch. Biochem. Biophys. 244 (2): 486–491.CrossRefGoogle Scholar
  15. 15.
    Conroy, D.M., P.J. Piper, and M.N. Samhoun. 1987. The effect of N-acetyl leukotriene E4 on guinea-pig airway smooth muscle in vitro. Br. J. Phannacol. 91: 365P. (Abstract)Google Scholar
  16. 16.
    Samhoun, M.N., D.M. Conroy, and P.J. Piper. 1988. Studies of the bronchoconstrictor actions of leukotrienes in vitro and their relevance to investigations in man. In Drugs affecting leukotrienes and lipoxygenase products–A potential fulfilled?. IBC Technical Services Ltd., London. 65–77.Google Scholar
  17. 17.
    Barnes, N.C., P.J. Piper, and J.F. Costello. 1984. Comparative actions of inhaled leukotriene C4, leukotriene D4 and histamine in normal human subjects. Thorax 39: 500–504.CrossRefGoogle Scholar
  18. 18.
    Barnes, N.C., and P.J. Piper. 1986. The actions of leukotrienes in human lung in vitro and in vivo. In The Leukotrienes: Their biological signficance. P.J. Piper, editor. Raven, Press, New York. 199–212.Google Scholar
  19. 19.
    Holroyde, M.C., R.E.C. Altounyan, A.H. Cole, M. Dixon, and E.V. Elliott. 1981. Bronchoconstriction produced in man by leukotrienes C and D. Lancet II: 17–18.Google Scholar
  20. 20.
    Arm, J.P., B.W. Spur, and T.H. Lee. 1987. Leukotriene E4 (LTE4) enhances airway histamine responsiveness in asthmatic subjects. Thorax 42: 220. (Abstract)Google Scholar
  21. 21.
    O’Driscoll, B.R.C., and A.B. Kay. 1982. Leukotrienes and lung disease. Thorax 37: 241.CrossRefGoogle Scholar
  22. 22.
    Zakrzewski, J.T., N.C. Barnes, J.F. Costello, and P.J. Piper. 1987. Lipid mediators in cystic fibrosis and chronic obstructive pulmonary disease. Am. Rev. resp. Dis. 136: 779–782.CrossRefGoogle Scholar
  23. 23.
    Black, P.N., R.W. Fuller, G.W. Taylor, P.J. Barnes, and C.T. Dollery. 1988. Bronchial reactivity is not increased after inhalation of leukotriene B4 and Prostaglandin D2. Br. J. Pharmacol. (In Press)Google Scholar
  24. 24.
    Lee, T.H., M.J. Walport, A.H. Wilkinson, M. Turner-Warwick, and A.B. Kay. 1981. Slow-reacting substance of anaphylaxis antagonist FPL-55712 in chronic asthma. Lancet 2: 304–305.CrossRefGoogle Scholar
  25. 25.
    Barnes, N.C., P.J..Piper, and J.F. Costello. 1987. The effect of an oral leukotriene antagonist L-649,923 on histamine and leukotriene D4-induced bronchoconstriction in normal man. J. Allergy Clin. Immunol. 79: 816–818.CrossRefGoogle Scholar
  26. 26.
    Britton, J.R., S.P. Hanley, and A.E. Tattersfield. 1987. The effect of an oral leukotriene D4 antagonist L-649,923 on the response to inhaled antigen in asthma. J. Allergy Clin. Immunol. 79: 811.CrossRefGoogle Scholar
  27. 27.
    Fleisch, J.H., L.E. Rinkema, C.A. Whitesitt, and W.S. Marshall. 1986.Pharmacologic antagonism of leukotriene mediated events. In The leukotrienes - their biological significance. P.J. Piper, editor. Raven Press, New York. 109–125.Google Scholar
  28. 28.
    Phillips, G.D., P. Rafferty, and S.T. Holgate. 1987. LY-171883 as an oral leukotriene D4 antagonist in non-asthmatic subjects. Thorax 42: 723.Google Scholar
  29. 29.
    Fleisch, J.H., M.L. Cloud, and W.S. Marshall. 1988. A brief review of preclinical and clinical studies with LY-171,883 and some comments on newer cysteinyl leukotriene receptor antagonists. Ann. NY Acad. Sci. 524: 356–368.CrossRefGoogle Scholar
  30. 30.
    Evans, J.M., N.C. Barnes, P.J. Piper, and J.F. Costello. 1988. The effect of a single dose of an inhaled leukotriene antagonist L-648,051 in mild asthma. Br. J. Clin. Pharmacol. (In Press)Google Scholar
  31. 31.
    Krell, R.D., R.E. Giles, Y.K. Yee, and D.W. Snyder. 1987. In vivo pharmacology of ICI 198,615: a novel potent and selective peptide leukotriene antagonist. J. Pharmacol. Exp. Ther. 243: 557–564.PubMedGoogle Scholar
  32. 32.
    Zamboni, R., M. Belley, E. Champion, L. Charette, R. Dehaven, R. Frenette, A.W. Ford-Hutchinson, J.Y Gauthier, and T.R. Jones. 1988. L-660,711, a potent orally active LTD4 antagonist. Adv. Prostaglandin, Thromboxane,Leukotriene Res. (In Press)Google Scholar
  33. 33.
    Hay, D.W.P., R.M. Muccitelli, S.S. Tucker, L.M. Vickery-Clark, and T.J. Torphy. 1987. Pharmacological profile of SK&F 104,353: a novel, potent and selective peptidoleukotriene receptor antagonist in guinea-pig and human airways. J. Pharmacol. Exp. Ther. 243: 474–481.Google Scholar
  34. 34.
    Evans, J.M., N.C. Barnes, J.T. Zakrzewski, H.P. Glenny, P.J. Piper, and J.F. Costello. 1988. Effects of an inhaled leukotriene (LT) antagonist, SK&F 104,353-Z2 on LTD4- and histamine-induced bronchoconstriction in normal man. Br. J. Pharmacol. (In Press)Google Scholar
  35. 35.
    Marone, G., A. Giordano, R. Cirillo, M. Triggiani, and C. Vigorito. 1988. Cardiovascular and metabolic effects of peptide leukotrienes in man. Ann. NY Acad. Sci. 524: 321–333.CrossRefGoogle Scholar
  36. 36.
    Letts, L.G., and P.J. Piper. 1982. The actions of leukotrienes C4 and D4 on guinea-pig isolated hearts. Br. J. Pharmacol. 76: 169–176.CrossRefGoogle Scholar
  37. 37.
    Levi, R. 1972. Effects of exogenous and immunologically released histamine on the isolated heart: a quantitative comparison. J. Pharmacol. Exp. Ther. 182: 227–238.PubMedGoogle Scholar
  38. 38.
    Liebig, R., W. Bernauer, and B.A. Peskar. 1975. Prostaglandin, slowreacting substance and histamine release from anaphylactic guinea-pig hearts and its pharmacological modification. Naunyn–Schmiedeberg’s Arch. Pharmacol. 289: 65–76.CrossRefGoogle Scholar
  39. 39.
    Allan, G., and R. Levi. 1981. Thromboxane and prostacyclin release during cardiac immediate hypersensitivity reactions in vitro. J. Pharmacol. Exp. Ther. 217: 57–61.Google Scholar
  40. 40.
    Piper, P.J., and H.B. Yaacob. 1988. Release of leukotrienes in cardiac anaphylaxis and its inhibition by a lipoxygenase inhibitor, CGS 8515. Br. J. Pharmacol. 93: 111 P.Google Scholar
  41. 41.
    Levi, R., J.A. Burke, Z-G. Guo, Y. Hattori, C.M. Happen, L.M. McManus, D.J. Hanahan, and R.N. Pinckard. 1984. Acetyl Glyceryl Ether Phosphorylcholine (AGEPC): A putative mediator of cardiac anaphylaxis in guinea pig.Circ. Res. 54:117–124.CrossRefGoogle Scholar
  42. 42.
    Piper, P.J., and A.G. Stewart. 1986. Coronary vasoconstriction in the rat, isolated perfused heart induced by platelet-activating factor is mediated by leukotriene C4. Br. J. Pharmacol. 88: 595–605.CrossRefGoogle Scholar
  43. 43.
    Yaacob, H.B., and P.J. Piper. 1988. ( UnPub )Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Priscilla J. Piper
    • 1
  • Marwa N. Samhoun
    • 1
  • Dolores M. Conroy
    • 1
  • H. B. Yaacob
    • 1
  • N. C. Barnes
    • 2
  • Jane M. Evans
    • 2
  • J. F. Costello
    • 2
  1. 1.Department of PharmacologyRoyal College of Surgeons of EnglandLondonUK
  2. 2.Department of Thoracic MedicineKings College School of Medicine and DentistryLondon SE5UK

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