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Updated: Jan 27, 2026
In Silico Clinical Trials for Cardiovascular Disease
Published on: May 27, 2022
Endothelins in cardiovascular biology and therapeutics
Neeraj Dhaun1,2, David J Webb3
1University of Edinburgh/British Heart Foundation Centre of Research Excellence, Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, UK. bean.dhaun@ed.ac.uk.
Insights
Endothelin-1 (ET-1) is a potent vasoconstrictor contributing to cardiovascular disease. Endothelin receptor antagonists show promise in treating various conditions, with novel therapies emerging.
Area of Science:
- Cardiovascular Medicine
- Endocrinology
- Pharmacology
Background:
- Cardiovascular disease is a leading cause of death globally, often resulting from chronic conditions.
- Endothelins are peptides that regulate cardiovascular function, with Endothelin-1 (ET-1) being a potent vasoconstrictor.
- ET-1 contributes to vasoconstriction, hypertrophy, inflammation, and the progression of cardiovascular diseases.
Purpose of the Study:
- To review the role of endothelins and their receptors in cardiovascular disease.
- To discuss the therapeutic potential of endothelin receptor antagonists.
- To explore emerging pharmacological strategies targeting the endothelin system.
Main Methods:
- Review of existing literature on endothelins and cardiovascular disease.
- Analysis of clinical trial data for endothelin receptor antagonists.
- Exploration of translational studies identifying new therapeutic targets.
Main Results:
- Endothelin receptor antagonists have transformed pulmonary arterial hypertension treatment.
- Ongoing trials investigate antagonists for resistant hypertension, chronic kidney disease, and antiangiogenic therapy support.
- Endothelin isoforms play critical roles in development, homeostasis, and cardiovascular/neuronal function.
Conclusions:
- Endothelin receptor antagonists are established therapies with expanding applications.
- Novel therapeutic approaches, including epigenetic modulators and biologics, are under development.
- Targeting the endothelin system offers significant potential for cardiovascular disease management.
Abstract:
Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The endothelins comprise three structurally similar peptides of 21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors - endothelin receptor type A (ETA) and endothelin receptor type B (ETB) - with equal affinity, whereas ET-3 has a lower affinity for ETA. ET-1 is the most potent vasoconstrictor in the human cardiovascular system and has remarkably long-lasting actions. ET-1 contributes to vasoconstriction, vascular and cardiac hypertrophy, inflammation, and to the development and progression of cardiovascular disease. Endothelin receptor antagonists have revolutionized the treatment of pulmonary arterial hypertension. Clinical trials continue to explore new applications of endothelin receptor antagonists, particularly in treatment-resistant hypertension, chronic kidney disease and patients receiving antiangiogenic therapies. Translational studies have identified important roles for the endothelin isoforms and new therapeutic targets during development, in fluid-electrolyte homeostasis, and in cardiovascular and neuronal function. Novel pharmacological strategies are emerging in the form of small-molecule epigenetic modulators, biologics (such as monoclonal antibodies for ETB) and possibly signalling pathway-biased agonists and antagonists.
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