RPB

Endothelin-1

ET-1, endothelin (the original 1988 isolate), preproendothelin-1 product; family members ET-2, ET-3; big endothelin-1 (the precursor); C-terminal pro-endothelin-1 (CT-proET-1, a blood test). Drugs acting on it: bosentan, ambrisentan, macitentan, aprocitentan, sparsentan, atrasentan, zibotentan (endothelin-receptor antagonists, "ERAs")

Cardiovascular & circulation
Awaiting medical reviewEN ES DE FR PT ZH+ Follow for updates

1What it is

Endothelin-1 was discovered in 1988 by Masashi Yanagisawa and colleagues in Japan, who isolated from cultured endothelial cells a peptide that constricted blood vessels more powerfully than anything known — about ten times more potent than angiotensin II, with an effect that lasted long after the peptide was washed away. It is made by cutting a 212-amino-acid precursor down to "big endothelin-1" (38 residues) and then, by endothelin-converting enzyme, to the active 21-amino-acid peptide. Endothelial cells release most of it towards the underlying smooth muscle rather than into the blood, so plasma levels are low and only loosely reflect what is happening in the vessel wall.

ET-1 is a physiological counterweight to nitric oxide and prostacyclin, the vessel-relaxing signals from the same cells. In health the balance keeps vessel tone appropriate. Under hypoxia, shear stress, inflammation, angiotensin II or insulin resistance, endothelial cells make more ET-1 and the balance tips towards constriction, wall thickening and fibrosis. That pathological role made it a drug target: blocking its receptors became a cornerstone of pulmonary arterial hypertension treatment from 2001 onwards, and since 2023 has expanded into resistant hypertension and proteinuric kidney disease.

Nobody administers endothelin-1 therapeutically. Its interest here is as the biology behind an important class of medicines, and as a biomarker. Community/self-directed use: essentially none documented, and none is plausible.

2How it's thought to work

Two receptors. ETA receptors on vascular smooth muscle cause constriction, cell growth and fibrosis — the harmful actions. ETB receptors on endothelial cells release nitric oxide and prostacyclin (a counter-regulatory, vessel-relaxing effect) and clear ET-1 from the circulation, particularly in the lungs; ETB receptors on smooth muscle also constrict. This dual role explains why some antagonists are ETA-selective (ambrisentan, atrasentan, zibotentan) while others block both (bosentan, macitentan, aprocitentan).
Signalling. Both receptors are Gq-coupled GPCRs; activation raises intracellular calcium (constriction) and activates MAP-kinase and growth pathways (remodelling). ETA binding is close to irreversible, which accounts for the long-lasting effect.
Kidney. ET-1 constricts renal vessels, reduces sodium excretion through ETA, but promotes sodium and water excretion through ETB in the collecting duct. In diabetic and IgA nephropathy, ETA-driven podocyte injury and glomerular inflammation contribute to protein leak — the rationale for sparsentan and atrasentan.
Other roles. ET-1 is a neuropeptide, modulates pain (it is involved in sickle-cell crisis and cancer pain), promotes tumour growth and in some cancers, and is essential in development — ET knockout mice die at birth with craniofacial and gut-nerve defects (Hirschsprung-type).
Endothelin-1, made by the endothelium itself, acting at the ETA receptor on the smooth muscle beneath it. It is among the most powerful and longest-lasting constrictors known, which is why the effect is so local and so sustained.Schematic — not to scale

3What the research shows

ET-1 infusion physiology in humans

Intra-arterial ET-1 produces slow-onset, sustained forearm vasoconstriction; ETA antagonists (e.g. BQ-123) cause vasodilation in healthy volunteers, proving tonic ET-1 activity contributes to normal vessel tone (Haynes & Webb 1994, Lancet). Systemic infusion raises blood pressure, lowers heart rate and reduces renal blood flow. These are small mechanistic studies; ET-1 is never given therapeutically. [2]

Endothelin-receptor antagonists in pulmonary arterial hypertension

Bosentan (BREATHE-1, Rubin 2002, NEJM) improved six-minute walk distance and delayed clinical worsening; ambrisentan (ARIES-1 and -2, Galiè 2008, Circulation) and macitentan (SERAPHIN, Pulido 2013, NEJM; 742 patients, 45% reduction in morbidity/mortality events) followed. ERAs are first-line therapy, usually combined with a PDE5 inhibitor (AMBITION, Galiè 2015, NEJM). [4][5][6]

Resistant hypertension

Aprocitentan, a dual ETA/ETB antagonist, lowered office systolic blood pressure by ~3.8 mmHg more than placebo at 4 weeks on top of standard triple therapy in PRECISION (Schlaich 2022, Lancet; n=730), with effect maintained to 48 weeks. FDA-approved as Tryvio in March 2024 — the first new class of antihypertensive in decades †. [7]

Proteinuric kidney disease

Sparsentan (dual ETA/angiotensin-II receptor antagonist) roughly halved proteinuria versus irbesartan in IgA nephropathy (PROTECT, Heerspink 2023, Lancet) and slowed eGFR decline over two years; FDA accelerated approval 2023, full approval 2024 †. Atrasentan (ETA-selective) reduced proteinuria by ~36% relative to placebo in IgA nephropathy (ALIGN, Heerspink 2025, NEJM) and received FDA accelerated approval as Vanrafia in April 2025 †. Earlier, atrasentan reduced kidney events in diabetic kidney disease (SONAR, Heerspink 2019, Lancet) but fluid retention limited enthusiasm; zibotentan plus dapagliflozin is in Phase 3 for CKD with high proteinuria (ZENITH programme) †. [8][9][10]

ET-1 as a biomarker

Plasma ET-1 and CT-proET-1 are raised in heart failure, pulmonary hypertension, sepsis, pre-eclampsia and sickle-cell disease and predict worse outcomes, but are not used for routine clinical decisions because plasma levels poorly reflect local vessel-wall activity.
Graded C/D

Cancer and pain

ETA antagonists (atrasentan, zibotentan) failed to improve survival in prostate cancer Phase 3 trials despite strong preclinical data (Nelson 2008, Cancer; ENTHUSE trials). Endothelin signalling in pain remains a research interest.

4Reported side effects and interactions

Literature-reported

Literature (ET-1 infusion). blood-pressure rise, reduced renal and coronary blood flow, chest tightness; in overdose in animals, coronary spasm and death. The peptide itself is toxic when given systemically in more than trace amounts.

Literature (receptor antagonists). fluid retention and peripheral oedema (the class effect, worst with ETA-selective agents in kidney disease and the reason SONAR enriched for fluid-tolerant patients); anaemia (haemodilution and other mechanisms); headache, nasal congestion, flushing; liver enzyme elevation (bosentan, requiring monthly liver tests; much less with ambrisentan and macitentan); decreased sperm counts. All ERAs are teratogenic — US labels carry boxed warnings and REMS programmes requiring pregnancy testing and contraception in people who can become pregnant †.

Community-reported

none documented.

Theoretical. long-term ETB blockade could impair ET-1 clearance and nitric-oxide release, a reason some developers favoured ETA selectivity; clinical significance unresolved.

Interactions. bosentan is a CYP3A4/2C9 inducer and lowers levels of many drugs (including hormonal contraceptives — a double problem given teratogenicity); cyclosporine and glibenclamide are contraindicated with bosentan; sparsentan is itself an angiotensin-receptor blocker and must not be combined with another ARB or ACE inhibitor; aprocitentan adds to the fluid-retention tendency of calcium-channel blockers and the hypotension of other antihypertensives.

Markers researchers commonly monitor

ET-1 itself is not given; these are the markers followed when its receptors are blocked, plus research measures:

MarkerWhy it's watched
Liver enzymes (ALT/AST) and bilirubinmonthly with bosentan; at baseline and as indicated with other ERAs.
Haemoglobin / haematocritERAs cause anaemia, usually mild, in the first months.
Body weight, oedema, NT-proBNPfluid retention is the key class risk, especially in kidney disease and heart failure.
Pregnancy testmonthly under US REMS programmes; teratogenicity is absolute.
eGFR, urine albumin-to-creatinine ratiothe efficacy readouts in kidney indications; an early small eGFR dip is expected.
Blood pressureefficacy in resistant hypertension; hypotension risk in combination.
Six-minute walk distance, echocardiography, right-heart catheterisationPAH outcome measures.
Plasma ET-1 / CT-proET-1research prognostic markers, not routine.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Endothelin-1 is a research-grade peptide for laboratory and clinical physiology use, supplied , stored frozen and dissolved immediately before use. It has no pharmaceutical presentation and must not be self-administered — it is a dangerous vasoconstrictor. Endothelin-receptor antagonists are oral tablets dispensed under prescription, several through restricted programmes. The site calculator is not applicable.

6Commonly studied alongside

Bosentan, ambrisentan, macitentan, aprocitentan, sparsentan, atrasentan, zibotentan (the antagonists); nitric oxide donors and PDE5 inhibitors (sildenafil, tadalafil) and prostacyclin analogues (the opposing pathway in pulmonary hypertension); angiotensin II and the natriuretic peptides (#167) as fellow vascular regulators; adrenomedullin and apelin (vasodilator peptides whose actions oppose ET-1); SGLT2 inhibitors (kidney-disease combination partners).

Informational cross-links. Not stack recommendations.

7Regulatory status by region

RegionStatus (checked —)
United StatesET-1 not a medicine. ERAs FDA-approved: bosentan (Tracleer, 2001), ambrisentan (Letairis, 2007), macitentan (Opsumit, 2013) for PAH; aprocitentan (Tryvio, March 2024) for resistant hypertension †; sparsentan (Filspari, accelerated 2023, full approval 2024) and atrasentan (Vanrafia, accelerated April 2025) for IgA nephropathy †
European UnionBosentan, ambrisentan, macitentan authorised for PAH; sparsentan (Filspari) authorised 2024 for IgA nephropathy †; aprocitentan (Jeraygo) authorised 2024 †; atrasentan under review or recently authorised †
United KingdomPAH ERAs licensed and NHS-commissioned via specialist centres; sparsentan and aprocitentan MHRA-licensed †
AustraliaPAH ERAs TGA-registered and PBS-listed; newer agents' status †
South AfricaBosentan and ambrisentan registered †; newer agents not registered †
SportEndothelin and its antagonists not listed by WADA

8Open questions

  • Can fluid retention be separated from the kidney-protective effect of ETA antagonism, perhaps by pairing with SGLT2 inhibitors?
  • Does ETA-selective or dual blockade matter clinically, after thirty years of debate?
  • Will ERAs extend to heart failure with preserved ejection fraction, sickle-cell disease or diabetic retinopathy, where ET-1 is implicated?
  • How much of the endothelin system's role in pain and cancer can be exploited, given the prostate-cancer failures?

9References

  1. 1Yanagisawa M et al. (1988). A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. PubMed · DOI
  2. 2Haynes WG, Webb DJ (1994). Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. PubMed · DOI
  3. 3Davenport AP et al. (2016). Endothelin. Pharmacol Rev. PubMed · DOI
  4. 4Rubin LJ et al. (2002). Bosentan therapy for pulmonary arterial hypertension (BREATHE-1). NEJM. PubMed · DOI
  5. 5Pulido T et al. (2013). Macitentan and morbidity and mortality in pulmonary arterial hypertension (SERAPHIN). NEJM. PubMed · DOI
  6. 6Galiè N et al. (2015). Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension (AMBITION). NEJM. PubMed · DOI
  7. 7Schlaich MP et al. (2022). Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial. Lancet. PubMed · DOI
  8. 8Heerspink HJL et al. (2023). Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial (PROTECT). Lancet. PubMed · DOI
  9. 9Heerspink HJL et al. (2019). Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. PubMed · DOI
  10. 10Heerspink HJL et al. (2025). Atrasentan in patients with IgA nephropathy (ALIGN). NEJM [verify]. PubMed · DOI
  11. 11Kohan DE, Barton M (2014). Endothelin and endothelin antagonists in chronic kidney disease. Kidney Int. PubMed · DOI
  12. 12US FDA. Prescribing information: Tryvio (aprocitentan), Filspari (sparsentan), Vanrafia (atrasentan), Tracleer (bosentan) — current labels [verify]. PubMed

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

30 Oct 2026Profile published — awaiting medical review

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