Skip to main content
Log in

What turns on the endothelins?

Inflammation Research Aims and scope Submit manuscript

Abstract

Production of the potent vasoconstrictor peptide endothelin-1 (ET-1) within the circulation is increased markedly in a numer of pathologies, such as the damage following from ischaemia and reperfusion, vasculitis, congestive heart failure, and systemic inflammatory response (septic shock syndrome) and related pathological states. All these conditions are associated with marked increases in the production of cytokines such as tumour necrosis factor-α and interleukin-2. Our experiments indicate that in rats administration of either of these cytokines results in a rapid increase in the circulating levels of ET-1 and a very pronounced ET-1-dependent coronary vasoconstriction. Furthermore, in rats suffering from adjuvant polyarthritis, in which there is marked joint inflammation and associated cytokine production, there are dramatic increases in coronary perfusion pressure which are absent when rats are treated with an endothelin receptor antagonist. This does not imply that inflammation must be associated with coronary vasoconstriction and myocardial dysfunction, but rather that in the rat, where ET-1 is a strong and almost irreversible constrictor of coronary vessels, coronary perfusion pressure serves as a very good bioassay for ET-1 activity. What our results do imply is that the ET-1 system is latent, but that in numerous disease states it can become rapidly upregulated following endothelial activation by cytokines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rubanyi GM, Polokoff MA. Endothelins: molecular biology, biochemistry, pharmacology, physiology and pathophysiology. Pharmacol Rev 1994;46:325–415.

    Google Scholar 

  2. Warner TD, Battistini B, Doherty AM, Corder R. Endothelin receptor antagonists: actions and rationale for their development. Biochem Pharmacol 1994;48:625–35.

    Google Scholar 

  3. Warner TD. Endothelin receptor antagonists. Pharmacol Drug Rev 1994;12:105–22.

    Google Scholar 

  4. Kiowski W, Sütsch G, Hunziker P, Müller P, Kim J, Oechslin E. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346:732–6.

    Google Scholar 

  5. Haynes WG, Webb DJ. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet 1994;344:852–4.

    Google Scholar 

  6. Vemulapalli S, Chiu PJS, Griscti K, Brown A, Kurowski S, Sybertz E. Phosphoramidon does not inhibit endogenous endothelin-1 release stimulated by hemorrhage, cytokines and hypoxia in rats. Eur J Pharmacol 1994;257:95–102.

    Google Scholar 

  7. Klemm P, Warner TD, Hohlfeld T, Corder R, Vane JR. Endothelin 1 mediates ex vivo coronary vasoconstriction caused by exogenous and endogenous cytokines. Proc Natl Acad Sci USA 1995;92:2691–5.

    Google Scholar 

  8. Heller RA, Krönke M. Tumor necrosis factor receptormediated signaling pathways. J Cell Biol 1994;126:5–9.

    Google Scholar 

  9. Arai K, Lee F, Miyajima A, Miyatake S, Arai N, Yokota T. Cytokines: coordinators of immune and inflammatory responses. Ann Rev Biochem 1990;59:783–94.

    Google Scholar 

  10. Arend WP, Dayer JM. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthr Rheum 1990;33:305–15.

    Google Scholar 

  11. Klemm P, Warner TD, Willis D, Moore AR, Vane JR. Coronary vasoconstriction in vitro in the hearts of polyarthritic rats: effectiveness of in vivo treatment with the endothelin receptor antagonist SB 209670. Br J Pharmacol 1995;114:1327–8.

    Google Scholar 

  12. Baydoun AR, Peers SH, Cirino G, Woodward B. Effects of endothelin-1 on the rat isolated heart. J Cardiovasc Pharmacol 1989;13Suppl 5:S193–6.

    Google Scholar 

  13. Warner TD. Endothelin receptor antagonists. Cardiovasc Drug Rev 1994;12:105–22.

    Google Scholar 

  14. Nose PS. Cytokines and reperfusion injury. J Cardiac Surg 1993;8Suppl 2:305–8.

    Google Scholar 

  15. Stenbergh WC, Tuttle TM, Makhoul RG, Bear HD, Sobel M, Fowler AA. Postischemic extremities exhibit immediate release of tumor necrosis factor. J. Vasc Surg 1994;20:474–81.

    Google Scholar 

  16. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, et al. Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 1994;25:1481–8.

    Google Scholar 

  17. Robertson CR, McCallum RM. Changing concepts in the pathophysiology of vasculitides. Curr Opinion Rheumatol 1994;6:3–10.

    Google Scholar 

  18. Savage CO, Cooke SP. The role of the endothelium in systemic vasculitis. J Autoimmun 1993;6:237–49.

    Google Scholar 

  19. Mann DL, Young JB. Basic mechanisms in congestive heart failure. Recognizing the role of proinflammatory cytokines. Chest 1994;105:897–904.

    Google Scholar 

  20. Hennig B, Diana JN, Toborek M, McClain CJ. Influence of nutrients and cytokines on endothelial cell metabolism. J Am Coll Nutr 1994;13:224–31.

    Google Scholar 

  21. Strieter RM, Kunkel SL, Bone RC. Role of tumor necrosis factor-α in disease states and inflammation. Crit Care Med 1993;21 Suppl 10:S447–63.

    Google Scholar 

  22. Gardiner SM, Kemp PA, March JE, Bennett T. Enhancement of the hypotensive and vasodilator effects of endotoxaemia in conscious rats by the endothelin antagonist, SB 209670. Br J Pharmacol 1995;116:1718–9.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

accepted by M. J. Parnham

Rights and permissions

Reprints and permissions

About this article

Cite this article

Warner, T.D., Klemm, P. What turns on the endothelins?. Inflamm Res 45, 51–53 (1996). https://doi.org/10.1007/BF02265115

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02265115

Key words

Navigation