Agents and Actions

, Volume 20, Issue 1–2, pp 124–132 | Cite as

Antagonism of the in vivo and in vitro effects of leukotriene D4 by SC-39070 in guinea pigs

  • G. W. Carnathan
  • J. H. Sanner
  • J. M. Thompson
  • C. M. Prusa
  • M. Miyano
Immunosuppression and Inflammation


Leukotriene D4 (LTD4) causes contractions of guinea pig isolated ilea, evokes pulmonary bronchoconstriction and induces lesions of the dermal vasculature. In the present study, we assessed the antagonism of these actions by SC-39070 compared to FPL-55712, a known LTD4 receptor antagonist. In guinea pig isolated ileum preparations, SC-39070 displayed selective antagonism of LTD4 with a pA2=8.20±0.06 (S.E.) and a Schild plot slope of −1.20. Administered intravenously to artificially-respired guinea pigs one minute prior to the agonist, SC-39070 antagonized (p<0.05) the bronchoconstrictive effect of LTD4 in a dose-dependent manner (0.5–10 mg/kg). At a dose of 2.0 mg/kg, i.v. this activity was retained through a 60 minute pretreatment interval. Similarly, after oral administration of SC-39070, there was a dose-dependent antagonism of the bronchoconstrictive activity of LTD4 (MED50=3.8 mg/kg). Antagonism of LTD4-induced bronchoconstriction was evidenced after oral administration of SC-39070 within one hour of treatment and efficacy was retained as long as 20 hours after treatment at a dose of 10 mg/kg. Finally, intravenously administered SC-39070 blocked LTD4-induced dermal permeability in guinea pigs with a minimum effective dose of 1.0 mg/kg. In each assay, the LTD4 antagonism evidence after treatment with SC-39070 appeared to be equal to or greater than that observed after treatment with FPL-55712.


Receptor Antagonist Oral Administration Effective Dose Minimum Effective Dose Plot Slope 
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]
    L. S. Orning, S. Hammarstrom and B. Samuelsson,Leukotriene D: A slow reacting substance from rat basophilic leukemia cells. Proc. Natl. Acad. Sci. USA77, 2014–2017 (1980).PubMedGoogle Scholar
  2. [2]
    R. A. Lewis, K. F. Austen, J. M. Drazen, D. A. Clark, A. Marfat and E. J. Corey,Slow reacting substances of anaphylaxis: Identification of leukotriences C-1 and D from human and rat sources Proc. Natl. Acad. Sci. USA77, 3710–3714 (1980).PubMedGoogle Scholar
  3. [3]
    B. M. Weichman, R. M. Muccitelli, R. R. Osborn, D. A. Holden, J. G. Gleason and M. A. Wasserman,In vitro and in vivo mechanisms of leukotriene-mediated bronchoconstriction in the guinea pig. J. Pharmac. exp. Ther.222, 202–208 (1982).Google Scholar
  4. [4]
    B. M. Weichman and S. S. Tucker,Contraction of guinea pig uterus by synthetic leukotrienes. Prostaglandins24, 245–253 (1982).PubMedGoogle Scholar
  5. [5]
    P. J. Piper and M. N. Samhoun,The mechanism, of action of leukotrienes C4 and D4 in guinea pig isolated perfused lung and parenchymal strips of guinea pig, rabbit and rat. Prostaglandins21, 793–803 (1981).PubMedGoogle Scholar
  6. [6]
    R. D. Krell, R. Osborn, L. Vickery, K. Falcone, M. O'Donnell, J. G. Gleason, C. Kinzig, and D. Bryan,Contraction of isolated airway smooth muscle by synthetic leukotrienes C 4 and D4. Prostaglandins22, 387–409, 1981.PubMedGoogle Scholar
  7. [7]
    J. M. Drazen, K. F. Austen, R. A. Lewis, D. A. G. Goto, A. Marfat and E. J. Corey,Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro. Proc. Natl. Acad. Sci USA77, 4354–4358 (1980).PubMedGoogle Scholar
  8. [8]
    J. H. Shelhamer, Z. Marom, F. Sun, M. K. Bach and M. Kaliner,The effects of arachinoids and leukotrienes on the release of mucus from human airways. Chest81, 365–375 (1982).Google Scholar
  9. [9]
    T. J. Williams and P. J. Piper,The action of chemically pure SRS-A on the microcirculation in vivo. Prostaglandins19, 779–789 (1980).PubMedGoogle Scholar
  10. [10]
    R. A. Lewis, J. M. Drazen, E. J. Corey and K. F. Austen,Structural and functional characteristics of the leukotriene components of slow reacting substance of anaphylaxis (SRS-A), in SRS-A and Leukotrienes (Ed. P. J. Piper), pp. 101–117, John Wiley & Sons, Ltd. Chichester (1981).Google Scholar
  11. [11]
    M. J. Peck, P. J. Piper and T. J. Williams,The effect of leukotrienes C 4 and D4 on the microvasculature of guinea pig skin. Prostaglandins21, 315–321 (1981).PubMedGoogle Scholar
  12. [12]
    D. E. Griswold, E. F. Webb, M. A. Clark and S. Mong,Phlogistic Activity of Leukotriene D4 in the Mouse. Inflammation10, 1–7 (1986).PubMedGoogle Scholar
  13. [13]
    J. Augstein, J. B. Farmer, T. B. Lee, P. Sheard and M. L. Tattersall,Selective inhibitor of slow reacting substance of anaphylaxis. Nature New Biol.245, 215–217 (1973).PubMedGoogle Scholar
  14. [14]
    N. Chand,FPL-55712-An antagonist of slow reacting substance of anaphylaxis: A review. Agents and Actions9, 133–140 (1979).PubMedGoogle Scholar
  15. [15]
    P. Sheard,Effects of anti-allergic compounds on SRS-A and leukotrienes, in SRS-A and Leukotrienes. (Ed. P. J. Piper), pp. 209–218, John Wiley and Sons, Ltd, Chichester (1981).Google Scholar
  16. [16]
    P. Sheard, M. C. Holroyde, A. M. Ghelani, J. R. Bantick and T. B. Lee,Antagonism of SRS-A and leukotrienes in Leukotrienes and Other Lipoxygenase Products (Eds. B. Samuelsson and R. Paoletti), pp. 229–235, Raven Press, New York (1982).Google Scholar
  17. [17]
    M. C. Holroyde and A. M. Ghelani,Kinetics of action of two leukotriene antagonists on guinea pig ileum. Eur J. Pharmac.90, 251–255 (1983).Google Scholar
  18. [18]
    D. M. Ritchie, J. N. Sierchio, R. J. Capetola and M. J. Rosenthal,SRS-A mediated bronchospasm by pharmacologic modification of lung anaphylaxis in vivo. Agents and Actions11, 396–401 (1981).PubMedGoogle Scholar
  19. [19]
    W. H. Anderson, M. O'Donnell, B. A. Simko and A. F. Welton,An in vivo model for measuring antigen-induced SRS-A mediated bronchoconstriction and plasma SRS-A levels in the guinea pig. Br. J. Pharmac.78, 67–74, 1983.Google Scholar
  20. [20]
    R. M. Muccitelli, R. R. Osborn and B. M. Weichman,Effect of inhibition of thromboxane production on the leukotriene D 4-mediated bronchoconstriction in the guinea pig. Prostaglandins26, 197–206 (1983).PubMedGoogle Scholar
  21. [21]
    P. Sheard, T. B. Lee and M. L. Tattersall,Further studies on the SRS-A antagonist FPL-55712. Monogr. Allergy12, 245–249 (1977).PubMedGoogle Scholar
  22. [22]
    J. H. Sanner,Antagonism of prostaglandin E 2 by 1-acetyl-2-(8-chloro-10,11-dihydrodibenz [b,f][1,4]oxazepine-10-carbonyl) hydrazine (SC-19220). Arch. Int. Pharmacodyn. Therap.180, 46–56 (1969).Google Scholar
  23. [23]
    R. J. Tallarida and L. S. Jacob,The Dose-Response Relation in Pharmacology. Springer-Verlag, New York (1979).Google Scholar
  24. [24]
    O. Arunlakshana and H. O. Schild,Some quantitative uses of drug antagonists. Br. J. Pharmac.15, 48–58 (1959).Google Scholar
  25. [25]
    R. G. D. Steel, and J. J. Torrie,Principles and Procedures of Statistics McGraw-Hill, New York (1960).Google Scholar
  26. [26]
    R. J. Tallarida and R. B. Murray,Manual of Pharmacologic Calculations with COmputer Programs. Springer-Verlag, New York, 1981.Google Scholar
  27. [27]
    H. R. Morris, G. W. Taylor, P. J. Piper, M. N. Samhoun and J. R. Tippens,Slow reacting substances (SRS): the structure and identification of SRSs from rat basophil leukemia (RBL-1) cells. Prostaglandins19, 185–201 (1980).PubMedGoogle Scholar
  28. [28]
    A. F. Welton, H. J. Crowley, D. A. Miller and B. Yaremko,Biological activities of a chemically synthesized form of leukotriene E4. Prostaglandins21, 287–296 (1981).PubMedGoogle Scholar
  29. [29]
    H. O. Schild,pA 2,a new scale for the measurement of drug antagonism. Br. J. Pharmac.2, 189–206 (1947).Google Scholar
  30. [30]
    J. H. Fleisch, L. E. Rinkema, K. D. Haisch, D. Swanson-Bean, T. Goodson, P. P. K. Ho and W. S. Marshall,LY171883, 1-[2-Hydroxy-3-Propyl-4-4-(1H-Tetrazol-5-YL)-Butoxyl] Phenyl-ethanone, an orally active leukotriene D 4 antagonist.J. Pharma. Exp. Thera. 233, 148–157 (1985).Google Scholar

Copyright information

© Birkhäuser Verlag 1987

Authors and Affiliations

  • G. W. Carnathan
    • 1
  • J. H. Sanner
    • 1
  • J. M. Thompson
    • 1
  • C. M. Prusa
    • 1
  • M. Miyano
    • 1
  1. 1.Departments of Biological Research and Medicinal ChemistrySearle Research and Development Division of G.D. Searle & Co.SkokieUSA

Personalised recommendations