Endothelin-1
ET-1, EDN1 gene product, preproendothelin-1 derived peptide
Endothelin-1 is a 21-residue peptide produced mainly by vascular endothelium and is the most potent endogenous vasoconstrictor known. Its discovery in 1988 launched an entire drug class, and endothelin receptor antagonists now hold approvals in pulmonary arterial hypertension, resistant hypertension and IgA nephropathy. The evidence for blocking the pathway is strong.
Mechanism
EDN1 encodes preproendothelin-1, processed to big endothelin-1 and then cleaved by endothelin-converting enzyme to the mature 21-residue peptide. The two disulfide bridges lock a rigid bicyclic core, and the free C-terminal tryptophan is indispensable. Secretion is largely abluminal and constitutive, so endothelin-1 acts as a local paracrine mediator on underlying smooth muscle rather than as a circulating hormone; plasma concentrations substantially underestimate tissue activity.
Two receptors give opposing effects. ETA, on vascular smooth muscle, couples to Gq/11 and G12/13, producing sustained vasoconstriction, proliferation and fibrosis. ETB has a dual role: endothelial ETB mediates nitric oxide and prostacyclin release with vasodilatation and is the main clearance receptor removing endothelin-1 from the circulation, while smooth muscle ETB contributes to constriction. This is why the choice between selective ETA blockade and dual ETA/ETB blockade is a genuine pharmacological question rather than a marketing distinction. The near-irreversible receptor binding explains why a peptide cleared in minutes produces vasoconstriction lasting an hour or more.
What the research shows
Blockade of this pathway has produced repeated phase 3 successes. Bosentan improved six-minute walk distance and delayed clinical worsening in pulmonary arterial hypertension in BREATHE-1. Macitentan went further in SERAPHIN, reducing a composite morbidity and mortality endpoint over long-term follow-up, which is a considerably stronger claim than exercise capacity alone. In resistant hypertension, the dual antagonist aprocitentan lowered blood pressure against placebo in the PRECISION trial. In IgA nephropathy, sparsentan, a dual endothelin and angiotensin receptor antagonist, reduced proteinuria by 49.8 per cent versus 15.1 per cent for irbesartan at 36 weeks, with two-year data showing benefit in chronic eGFR slope.
The failures are instructive and substantial. Sitaxentan was withdrawn worldwide after fatal hepatotoxicity. Bosentan carries dose-dependent hepatotoxicity requiring monthly liver monitoring, and all agents in the class are potently teratogenic, requiring pregnancy prevention programmes. Endothelin antagonists failed in chronic heart failure, where fluid retention proved limiting, and darusentan disappointed in resistant hypertension before aprocitentan succeeded. Zibotentan failed in phase 3 trials in prostate cancer. Fluid retention and anaemia are class effects seen consistently across indications.
Evidence assessment
High-quality evidence
Six citations survived audit with every identifier verified, including five separate pivotal phase 3 randomised trials in the New England Journal of Medicine and the Lancet, covering morbidity and mortality endpoints in pulmonary arterial hypertension and hard renal endpoints in IgA nephropathy. Multiple agents hold both FDA and MHRA approval.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A novel potent vasoconstrictor peptide produced by vascular endothelial cells Preclinical only
Identified endothelin as the most potent vasoconstrictor peptide then known, founding an entire field and drug class.
Bosentan therapy for pulmonary arterial hypertension Preclinical only
Bosentan improved six-minute walk distance and delayed clinical worsening, the first registration trial for an endothelin receptor antagonist.
Macitentan and morbidity and mortality in pulmonary arterial hypertension Preclinical only
Macitentan significantly reduced a composite morbidity and mortality endpoint, moving the class beyond exercise-capacity endpoints.
Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial Preclinical only
Proteinuria fell 49.8 per cent with sparsentan versus 15.1 per cent with irbesartan at 36 weeks, supporting accelerated approval on a surrogate endpoint.
Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial Preclinical only
Sustained proteinuria reduction with benefit in chronic eGFR slope, supporting kidney preservation rather than a proteinuria effect alone.
Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial Preclinical only
Aprocitentan lowered blood pressure versus placebo in resistant hypertension, extending the class into a new indication.
Safety
Endothelin-1 itself is not therapeutic; infusion causes marked and prolonged vasoconstriction and hypertension. The antagonist class carries well-defined risks: embryo-fetal toxicity requiring contraception and pregnancy testing programmes, hepatotoxicity (severe with bosentan, fatal with the withdrawn sitaxentan), fluid retention and peripheral oedema, anaemia, and reduced sperm counts. These are prescription medicines requiring monitoring, and none should be regarded as benign.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Bosentan, ambrisentan and macitentan hold MHRA authorisation for pulmonary arterial hypertension, and sparsentan is authorised for IgA nephropathy, all with pregnancy prevention requirements. Sitaxentan was withdrawn from the UK and worldwide in 2010 after fatal liver injury. Endothelin-1 itself is unlicensed. |
| United States | Endothelin-1 itself is not approved. FDA-approved endothelin receptor antagonists include bosentan, ambrisentan and macitentan for pulmonary arterial hypertension, aprocitentan for resistant hypertension and sparsentan for IgA nephropathy, several under Risk Evaluation and Mitigation Strategy programmes. |
| WADA (sport) | Neither endothelin-1 nor endothelin receptor antagonists appear on the WADA Prohibited List. The peptide itself, lacking approval for human therapeutic use, would fall under section S0. |
Questions
ETA drives vasoconstriction and fibrosis, while endothelial ETB causes vasodilatation and clears endothelin from blood. Selective ETA blockade preserves that clearance and vasodilator role; dual blockade may give more complete constriction blockade. Both approaches have succeeded in trials.
They are effective prescription medicines with real risks. All are potently teratogenic and require pregnancy prevention programmes. Bosentan causes dose-dependent liver injury needing monthly monitoring, and sitaxentan was withdrawn worldwide after fatal hepatotoxicity.