Endothelin: 30 Years From Discovery to Therapy

Hypertension. 2019 Dec;74(6):1232-1265. doi: 10.1161/HYPERTENSIONAHA.119.12105. Epub 2019 Nov 4.


Discovered in 1987 as a potent endothelial cell-derived vasoconstrictor peptide, endothelin-1 (ET-1), the predominant member of the endothelin peptide family, is now recognized as a multifunctional peptide with cytokine-like activity contributing to almost all aspects of physiology and cell function. More than 30 000 scientific articles on endothelin were published over the past 3 decades, leading to the development and subsequent regulatory approval of a new class of therapeutics-the endothelin receptor antagonists (ERAs). This article reviews the history of the discovery of endothelin and its role in genetics, physiology, and disease. Here, we summarize the main clinical trials using ERAs and discuss the role of endothelin in cardiovascular diseases such as arterial hypertension, preecclampsia, coronary atherosclerosis, myocardial infarction in the absence of obstructive coronary artery disease (MINOCA) caused by spontaneous coronary artery dissection (SCAD), Takotsubo syndrome, and heart failure. We also discuss how endothelins contributes to diabetic kidney disease and focal segmental glomerulosclerosis, pulmonary arterial hypertension, as well as cancer, immune disorders, and allograft rejection (which all involve ETA autoantibodies), and neurological diseases. The application of ERAs, dual endothelin receptor/angiotensin receptor antagonists (DARAs), selective ETB agonists, novel biologics such as receptor-targeting antibodies, or immunization against ETA receptors holds the potential to slow the progression or even reverse chronic noncommunicable diseases. Future clinical studies will show whether targeting endothelin receptors can prevent or reduce disability from disease and improve clinical outcome, quality of life, and survival in patients.

Keywords: clinical trial; coronary artery disease; heart failure; lung diseases; molecular biology; pharmacology; renal insufficiency, chronic.

Publication types

  • Historical Article
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cardiovascular Diseases / drug therapy
  • Cardiovascular Diseases / physiopathology*
  • Clinical Trials as Topic
  • Coronary Artery Disease / drug therapy
  • Coronary Artery Disease / physiopathology
  • Endothelins / biosynthesis*
  • Endothelins / drug effects
  • Endothelins / history*
  • Female
  • Follow-Up Studies
  • History, 20th Century
  • Humans
  • Hypertension / drug therapy
  • Hypertension / physiopathology
  • Male
  • Receptors, Endothelin / drug effects
  • Renal Artery Obstruction / drug therapy
  • Renal Artery Obstruction / physiopathology
  • Risk Assessment


  • Endothelins
  • Receptors, Endothelin