Article Text

Download PDFPDF
Endothelin antagonism in pulmonary hypertension, heart failure, and beyond
  1. T Attinà1,
  2. R Camidge1,
  3. D E Newby2,
  4. D J Webb1
  1. 1Clinical Research Centre, Department of Medical Sciences, University of Edinburgh, Edinburgh, UK
  2. 2Department of Cardiology, Royal Infirmary, Edinburgh, UK
  1. Correspondence to:
    Professor David J Webb
    Clinical Research Centre, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK;

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

The discovery in 1988 of endothelin-1 (ET-1) by Yanagisawa and colleagues in Japan represented a landmark in the field of cardiovascular research.1 A combination of molecular and pharmacological approaches revealed ET-1 as the most powerful vasoconstrictor yet identified in biological systems. Since its discovery, a great deal of effort has been made towards gaining a better understanding of the key roles—developmental, physiological, and pathological—played by this peptide, particularly with regard to the cardiovascular system. In this review, we will describe current knowledge on the endothelin system and focus on the cardiovascular effects of ET-1 and its antagonism. We will review the evidence for the two therapeutic areas mainly investigated, pulmonary arterial hypertension and heart failure, as well as outline its important role in hypertension, renal dysfunction, and atherosclerosis.


Endothelin synthesis and clearance

The endothelin family consists of three closely related peptides, ET-1, ET-2, and ET-3, each 21 amino acids in length and derived from separate genes. ET-1[1–21] is the main isoform produced in the cardiovascular system and about which most is known; ET-2 is mainly produced within the kidney and intestine, whereas ET-3 is predominantly found within the central nervous system (tables 1 and 2). However, the roles of ET-2 and ET-3, except in embryonic development, remain unclear.

View this table:
Table 1

 Sites of production of ET-1, ET-2, and ET-3

View this table:
Table 2

 Classification of endothelin receptors

ET-1 is not stored and released but instead generated in response to a range of stimuli, which vary between different tissues (fig 1).2 It is generated mainly in endothelial cells of blood vessels and requires several processing steps before the mature peptide is formed (fig 1). The final step in the ET-1 pathway involves cleavage of the 38 amino acid “big ET-1” by the highly selective membrane bound metalloproteinase, endothelin converting enzyme (ECE-1). ECE independent pathways of ET-1 formation have also …

View Full Text


  • Competing interest statement: Professor Webb has, in the past, provided advice to pharmaceutical companies (Abbott, Actelion, Astra Zeneca, BMS, Encysive, Roche) on the clinical development of endothelin antagonists for cardiovascular disease.

Linked Articles

  • Miscellanea
    BMJ Publishing Group Ltd and British Cardiovascular Society