Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist

Nature volume 365, pages 759–761 (1993)Cite this article

Abstract

SINCE its discovery1, endothelin-1 has attracted considerable scientific interest because of its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors2. Plasma concentrations of endothelin-1 are low3 and its release by endothelial cells is polarized towards the basolateral side4,5, suggesting that it is a paracrine factor and not a hormone. Consequently, the effect of injected endothelin-1 may not reflect the effect of endogenous endothelin-1. In contrast, blockade of the action of endogenous endothelin-1 using receptor antagonists should be a valuable means of investigating its physiological and pathological effects. We report here evidence for the pathophysiological role of endothelin-1 as brought by the first synthetic orally active non-peptide antagonist of endothelin receptors, Ro 46-2005.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Yanagisawa, M. et al. Nature 332, 411–415 (1988).

    Article  ADS  CAS  Google Scholar 

  2. Kasuya, Y., Takuwa, Y., Yanagisawa, M., Masaki, T. & Goto, K. Br. J. Pharmac. 107, 456–462 (1992).

    Article  CAS  Google Scholar 

  3. Ando, K., Hirata, Y., Shichiri, M., Emori, T. & Marumo, F. FEBS Lett. 245, 164–166 (1989).

    Article  CAS  Google Scholar 

  4. Wagner, F. et al. J. biol. Chem. 267, 16066–16068 (1992).

    CAS  PubMed  Google Scholar 

  5. Yoshimoto, S. et al. J. cardiovasc. Pharmac. 17(suppl.7), S260–S263 (1991).

    Article  CAS  Google Scholar 

  6. Arai, H., Hori, S., Aramori, I., Ohkubo, H. & Nakanishi, S. Nature 348, 730–732 (1990).

    Article  ADS  CAS  Google Scholar 

  7. Sakurai, T. et al. Nature 348, 732–735 (1990).

    Article  ADS  CAS  Google Scholar 

  8. Emori, T., Hirata, Y. & Marumo, F. FEBS Lett. 263, 261–264 (1990).

    Article  CAS  Google Scholar 

  9. Sokolovsky, M., Ambar, I. & Galron, R. J. biol. Chem. 267, 20551–20554 (1992).

    CAS  PubMed  Google Scholar 

  10. Ihara, M. et al. Life Sci. 50, 247–255 (1993).

    Article  Google Scholar 

  11. Takayanagi, R. et al. FEBS Lett. 282, 103–106 (1991).

    Article  CAS  Google Scholar 

  12. Clozel, M., Gray, G. A. & Breu, V. Biochem. biophys. Res. Commun. 186, 867–873 (1992).

    Article  CAS  Google Scholar 

  13. Moreland, S., McMullen, D. M. Delaney, C. L., Lee, V. G. & Hunt, J. T. Biochem. biophys. Res. Commun. 184, 100–106 (1992).

    Article  CAS  Google Scholar 

  14. McMurdo, L., Corder, R., Thiemermann, C. & Vane, J. R. Br. J. Pharmac. 108, 557–561 (1993).

    Article  CAS  Google Scholar 

  15. Harrison, V. J., Randriantsoa, A. & Schoeffter, Ph. Br. J. Pharmac. 105, 511–513 (1992).

    Article  CAS  Google Scholar 

  16. Lerman, A. et al. New Engl. J. Med. 325, 997–1001 (1991).

    Article  CAS  Google Scholar 

  17. McMurray, J. J. et al. Circulation 85, 1374–1379 (1992).

    Article  CAS  Google Scholar 

  18. Dohi, Y. & Lüscher, T. F. Hypertension 18, 543–549 (1991).

    Article  CAS  Google Scholar 

  19. Fischli, W., Clozel, M. & Guilly, C. Life Sci. 44, 1429–1436 (1989).

    Article  CAS  Google Scholar 

  20. Arunlakshana, O. & Schild, H. O. Br. J. Pharmac. Chemother. 14, 48–58 (1959).

    Article  CAS  Google Scholar 

  21. Williams, D. L. Jr, Jones, K. L., Pettibone, D. J., Lis, E. V. & Clineschmidt, B. V. Biochem. biophys. Res. Commun. 175, 556–561 (1991).

    Article  CAS  Google Scholar 

  22. Clozel, M., Löffler, B.-M. & Gloor, H. J. cardiovasc. Pharmac. 17(suppl. 7), S313–S315 (1991).

    Article  CAS  Google Scholar 

  23. Mino, N. et al. Eur. J. Pharmac. 221, 77–83 (1992).

    Article  CAS  Google Scholar 

  24. Webb, M. L. et al. Biochem. biophys. Res. Commun. 185, 887–892 (1992).

    Article  CAS  Google Scholar 

  25. Clozel, M. & Watanabe, H. Life Sci. 52, 825–834 (1993).

    Article  CAS  Google Scholar 

  26. Solomon, R. A. et al. Stroke 16, 58–64 (1985).

    Article  CAS  Google Scholar 

  27. Suzuki, R. et al. J. Neurosurg. 77, 96–100 (1992).

    Article  CAS  Google Scholar 

  28. Clozel, M. J. Hypertension 7, 913–917 (1989).

    Article  CAS  Google Scholar 

  29. Mulvany, M. J. & Halpern, W. Circ. Res. 41, 19–26 (1977).

    Article  CAS  Google Scholar 

  30. Heymann, M. A. & Payne, B. D., Hoffman, J. I. E. & Rudolph, A. M. Progr. cardiovasc. Dis. 20, 55–79 (1977).

    Article  CAS  Google Scholar 

  31. Clozel, J. P., Fischli, W. & Ménard, J. J. Hypertension 11, 75–81 (1993).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4002, Basel, Switzerland

    Martine Clozel, Volker Breu, Kaspar Burri, Jean-Marie Cassal, Walter Fischli, Gillian A. Gray, Georges Hirth, Bernd-Michael Löffier, Marcel Müller, Werner Neidhart & Henri Ramuz

Authors
  1. Martine Clozel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Volker Breu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaspar Burri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean-Marie Cassal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Walter Fischli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gillian A. Gray
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Georges Hirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bernd-Michael Löffier
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Marcel Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Werner Neidhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Henri Ramuz
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clozel, M., Breu, V., Burri, K. et al. Pathophysiological role of endothelin revealed by the first orally active endothelin receptor antagonist. Nature 365, 759–761 (1993). https://doi.org/10.1038/365759a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/365759a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing