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  • Review Article
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New therapeutics that antagonize endothelin: promises and frustrations

Nature Reviews Drug Discovery volume 1, pages 986–1001 (2002)Cite this article

Key Points

  • The vascular endothelium synthesizes and releases a range of vasodilators and vasoconstrictors that have key roles in the local regulation of vascular tone.

  • Endothelin (ET) — a highly potent peptidic vasoconstrictor — regulates blood pressure through effects on blood vessels, heart and kidneys.

  • The ET system can be overactive in disorders such as hypertension, heart failure and renal disease, and considerable efforts have been made to develop antagonists of its actions in the hope that they would have therapeutic potential.

  • ET-1 is the predominant isoform of the ET peptide family, which also includes ET-2 and ET-3. The biological activity of ET-1 is regulated by a complex process of synthesis and breakdown.

  • The effects of ET are mediated by binding to G-protein-coupled receptors. So far, two types of ET receptor have been identified in humans. The ET type-A receptor (ETA) has higher binding affinity for ET-1 and ET-2 than for ET-3, whereas the type-B receptor (ETB) binds the three isopeptides with comparable affinity.

  • Once ETs and the ET receptors had been identified, many companies set up screens for antagonists, which are classified as either ETA - or ETB -receptor selective, or mixed antagonists. Most are either ETA -receptor selective or mixed antagonists. Non-peptide antagonists of each type have been developed, and many are orally bioavailable.

  • any antagonists showed promising results in animal models of renal disease, hypertension, heart failure and more recently, several types of cancer.

  • However, results in human trials have generally been less exciting than hoped. Trial results in several areas are described, including arterial hypertension, congestive heart failure and chronic renal failure, and possible approaches to maximizing the potential of ET antagonism in these and other novel indications, such as secondary hyperparathyroidism, are discussed.

Abstract

The discovery of endothelin — a highly potent endogenous vasoconstrictor — in 1988 has led to considerable efforts to develop antagonists of endothelin receptors that could have therapeutic potential in disorders including hypertension, heart failure and renal diseases. However, in general, the results of trials in humans have not mirrored the highly promising effects in animal disease models. Here, we discuss preclinical and clinical results with endothelin antagonists, and consider possible approaches to fully realizing the potential of endothelin antagonism.

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Figure 1: Regulation of ET-1 synthesis, pathway of ET generation and ET-receptor-mediated actions on smooth muscle cells.
Figure 2: Mechanisms of signalling induced by ET-1 through ETA and ETB receptors.
Figure 3

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Acknowledgements

The authors gratefully acknowledge the Comitato 30 Ore per la Vita (Rome, Italy) and the Banca Popolare di Bergamo–Credito Varesino (Bergamo, Italy), A. Piccinelli for the invaluable assistance in drawing the figures and M. Passera for the help in preparing the manuscript.

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Authors and Affiliations

  1. Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, Bergamo, 24125, Italy

    Giuseppe Remuzzi, Norberto Perico & Ariela Benigni

  2. Department of Medicine and Transplantation, Ospedali Riuniti Bergamo, Largo Barozzi 1, Bergamo, 24128, Italy

    Giuseppe Remuzzi

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  1. Giuseppe Remuzzi
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Correspondence to Giuseppe Remuzzi.

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DATABASES

Cancer.gov

prostate cancer

LocusLink

ACE

angiotensin

AT1 receptor

ECE-1

ETA receptor

ETB receptor

ET-1

ET-2

ET-3

Fos

IL-1

Jun

neutral endopeptidase

phosphodiesterase type 5

TGF-β

FURTHER INFORMATION

World Health Organization

Glossary

WEIBEL–PALADE BODIES

Storage granules present in endothelial cells.

MALIGNANT HAEMANGIOENDOTHELIOMA

A rare vascular neoplasm of endothelial-cell proliferation.

AUTOCRINE

Describing an agent secreted from a cell that acts on the cell in which it is produced.

PARACRINE

Describing an agent secreted from a cell that acts on other cells in the local environment.

CARDIAC INDEX

The cardiac output divided by body surface area.

BORG DYSPNOEA INDEX

A measure of perceived breathlessness on a scale of 0 to 10, with higher values indicating more severe dyspnoea.

WORLD HEALTH ORGANIZATION FUNCTIONAL CLASS

A classification of pulmonary hypertension according to a modification of the New York Heart Association (NYHA) class, with higher classes indicating more severe disease.

PROTEINURIA

The excretion rate of total proteins in urine.

RENIN–ANGIOTENSIN SYSTEM

A key regulator of blood pressure. Renin cleaves the protein angiotensinogen to produce the inactive peptide angiotensin I. This is cleaved by the angiotensin-converting enzyme (ACE) to give the peptide angiotensin II, which activates the angiotensin II type 1 (AT1) receptor, leading to various effects, including vasoconstriction.

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Remuzzi, G., Perico, N. & Benigni, A. New therapeutics that antagonize endothelin: promises and frustrations. Nat Rev Drug Discov 1, 986–1001 (2002). https://doi.org/10.1038/nrd962

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