Endothelin-1
One of the most potent vessel constrictors the body makes, studied mostly by blocking it
Endothelin-1 is a 21-amino-acid peptide released by the lining of blood vessels that constricts them powerfully. It is never given as a treatment. Drugs that block its receptors are approved for pulmonary arterial hypertension; giving it to people has been done only in experiments, which is where its human data come from.
What is it?
Endothelin-1 was discovered almost 40 years ago as a peptide made by the endothelium, the cell layer lining blood vessels, and it remains one of the most potent vasoconstrictors known. It also acts on airways, kidneys and pain nerves. Its significance in medicine runs through the drugs that block it: endothelin receptor antagonists are approved for pulmonary arterial hypertension and, with aprocitentan (Tryvio), for resistant hypertension, while trials in many other diseases have failed.
Giving it to people is done only to test a hypothesis. In asthma, inhaled endothelin-1 produced rapid, dose-dependent bronchoconstriction in all eight asthmatics tested and none in healthy volunteers, reversed quickly by albuterol. That made it a candidate driver of asthma.
In migraine with aura, the theory was that endothelin released from irritated vessels triggers the aura. Fourteen patients received a high-dose intravenous infusion against placebo in a crossover trial, and none developed aura or migraine headache.
As a blood marker it has also disappointed: in complex regional pain syndrome, plasma endothelin-1 did not differ from patients with other pain or from healthy volunteers.
Infusions in healthy people show where it acts. In the kidneys it cut blood flow by a third and sodium excretion by more than half; in the brain, the narrowing of the middle cerebral artery tracked the rise in blood pressure rather than a direct effect on cerebral blood flow.
As a prognostic marker, though, it performs better than as a diagnostic one. Across 30,181 patients with coronary disease, the highest ET-1 levels carried nearly four times the risk of death, and higher levels predicted heart failure in kidney disease and cardiovascular death in hospitalised heart failure even after NT-proBNP. It is raised in diabetic retinopathy, glaucoma and systemic sclerosis, but in suspected pulmonary embolism it added nothing to D-dimer.
Blocking its receptors in healthy men blunted blood pressure responses to changes in oxygen, and dietary salt raised urinary ET-1 in women but not men, two clues to how it sets pressure. Not every antagonist trial has worked: macitentan did not ease coronary vasospasm in a small placebo-controlled trial.
Mechanism of Action
Endothelin-1 is a peptide made by the endothelium and one of the most potent vasoconstrictors known; it also acts on airways, kidneys and pain nerves.
Vasoconstriction
Infused, it cut kidney blood flow by a third and narrowed brain arteries in step with blood pressure.
Airways
Inhaled, it constricted the airways of asthmatics but not healthy volunteers.
Antagonist drugs
Blocking its receptors treats pulmonary arterial hypertension and, with aprocitentan, resistant hypertension.
Published Research
These are the studies that describe endothelin-1 in people, read from their PubMed abstracts: two challenge studies, a marker study and a review.
Inhaled in asthma
8 asthmatics and 5 healthy volunteers inhaled endothelin-1. Every asthmatic had rapid, dose-dependent bronchoconstriction, reversed completely by albuterol; none of the healthy volunteers did, and oxygen saturation did not change.
Infused in migraine with aura
14 patients with migraine with aura received 8 ng/kg/min intravenously for 20 minutes or placebo, crossover and double-blind. None had aura or migraine headache within 24 hours, and no serious adverse events occurred.
Not a pain marker
Plasma endothelin-1 in 20 patients with severe complex regional pain syndrome did not differ from 8 patients with other chronic pain or 10 healthy volunteers, so it cannot serve as a diagnostic marker.
The brain's arteries on MRI
In a randomised crossover study in 14 healthy volunteers, high-dose intravenous endothelin-1 raised mean arterial pressure by 14% and narrowed the middle cerebral artery by 5%, without changing cerebral blood flow or oxygen use, pointing to an effect of blood pressure rather than direct constriction.
The kidneys in healthy men
In nine healthy men, endothelin-1 infused at 2.5 ng/kg per minute cut glomerular filtration by 11%, renal blood flow by 35% and sodium excretion by 58%; an ETA-receptor blocker reversed these effects only partly.
Chronic kidney disease with diabetes
In patients with CKD, diabetes and anaemia, each log-unit higher ET-1 was associated with more kidney events (HR 1.61) and heart failure (HR 2.61), but not with death.
Hospitalised heart failure
In 4,368 patients hospitalised for heart failure, higher big ET-1 independently predicted cardiovascular death, even after adjustment for NT-proBNP.
Pulmonary embolism
ET-1 was higher in confirmed pulmonary embolism but discriminated worse than D-dimer and added nothing significant to it.
Blood pressure and oxygen sensing
In healthy young men, blocking endothelin receptors with bosentan blunted the blood pressure responses to both low and high oxygen, suggesting ET-1 helps set resting pressure.
Salt and sex differences
In salt-resistant adults, higher sodium intake increased urinary ET-1 in women but not men.
Macitentan in coronary vasospasm
In 28 patients with coronary artery spasm, adding the endothelin receptor antagonist macitentan did not reduce angina burden against placebo.
Endothelin-1 in health and disease
A review of how endothelin-1 is made, stored and released, its roles in cardiovascular disease, COVID-19 and chronic pain, and why receptor antagonists succeeded in pulmonary hypertension and mostly failed elsewhere.
Prognosis in coronary disease
Across studies of 30,181 patients with coronary artery disease, the highest ET-1 levels carried a 3.77-fold risk of death and 2.24-fold risk of major cardiac events against the lowest; big ET-1 and CT-proET-1 also predicted events.
Diabetic retinopathy
Ten studies found circulating ET-1 higher in diabetic retinopathy than in healthy people or diabetic patients without retinopathy.
Glaucoma
Across 23 studies with 2,597 people, plasma ET-1 was higher in open-angle, normal-tension and angle-closure glaucoma than in controls.
Systemic sclerosis
Across 26 studies, ET-1 was higher in systemic sclerosis than in controls, with moderate certainty, but did not separate disease subtypes or complications.
Aprocitentan for resistant hypertension
A review describes aprocitentan, a dual endothelin receptor antagonist, and the phase 3 trial in which it lowered blood pressure in resistant hypertension.
Dosing Data
Endothelin-1 is never a treatment. Research studies infuse tiny amounts to test hypotheses under monitoring.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the challenge studies; it is never given as treatment.
Contraindications & Cautions
Not a treatment.
Legal Status
Endothelin-1 is not a medicine anywhere.
Frequently Asked Questions
?What is endothelin-1?
A 21-amino-acid peptide made by blood vessel linings that constricts vessels powerfully.
?Is it used as a drug?
No. Drugs that block its receptors are approved for pulmonary arterial hypertension; endothelin-1 itself is only given in experiments.
?Does it cause migraine aura?
An intravenous challenge in 14 patients with migraine with aura triggered no auras.
?Is it linked to asthma?
Inhaled, it constricted the airways of all eight asthmatics tested and none of five healthy volunteers.
?Is endothelin-1 a useful blood test?
For prognosis, sometimes: high levels predicted death and cardiac events in coronary disease and cardiovascular death in heart failure. For diagnosis it is weaker; in suspected pulmonary embolism it added nothing to D-dimer.
?Which drugs block endothelin?
Endothelin receptor antagonists are approved for pulmonary arterial hypertension, and aprocitentan (Tryvio) has a US label for resistant hypertension.
References
- [pubmed] Chalmers GW, et al. "Endothelin-1-induced bronchoconstriction in asthma." Am J Respir Crit Care Med, 1997;156(2 Pt 1):382-8. PMID: 9279213.
- [pubmed] Hougaard A, et al. "Intravenous Endothelin-1 Infusion Does Not Induce Aura or Headache in Migraine Patients With Aura." Headache, 2020;60(4):724-734. PMID: 31994720.
- [pubmed] Eisenberg E, et al. "Plasma endothelin-1 levels in patients with complex regional pain syndrome." Eur J Pain, 2004;8(6):533-8. PMID: 15531221.
- [pubmed] Banecki KMRM, et al. "Endothelin-1 in Health and Disease." Int J Mol Sci, 2023;24(14). PMID: 37511055.
- [pubmed] Yanagisawa M, et al. "A novel potent vasoconstrictor peptide produced by vascular endothelial cells." Nature, 1988;332(6163):411-5. PMID: 2451132.
- [pubmed] Davenport AP, et al. "Endothelin." Pharmacol Rev, 2016;68(2):357-418. PMID: 26956245.
- [pubmed] Weitzberg E. "Circulatory responses to endothelin-1 and nitric oxide with special reference to endotoxin shock and nitric oxide inhalation." Acta Physiol Scand Suppl, 1993;611:1-72. PMID: 8379340.
- [other] US FDA, Drugs@FDA (openFDA): no application for endothelin-1. Read September 30, 2026.
- [clinical-trial] Hougaard A, et al. "Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers." J Cereb Blood Flow Metab, 2020;40(8):1685-1694. PMID: 31500524.
- [clinical-trial] Vuurmans JL, et al. "Effects of endothelin-1 and endothelin-1-receptor blockade on renal function in humans." Nephrol Dial Transplant, 2004;19(11):2742-6. PMID: 15328386.
- [pubmed] Wang H, et al. "Prognostic Value of Endothelin-1 or Related Peptides in Patients With Coronary Artery Disease: A Systematic Review and Meta-Analysis." Angiology, 2025;76(2):108-116. PMID: 38128149.
- [pubmed] Mc Causland FR, et al. "Endothelin-1 and Cardio-Kidney Events among Patients with Chronic Kidney Disease, Diabetes, and Anemia." Am J Nephrol, 2025:1-11. PMID: 41183011.
- [pubmed] Wang J, et al. "Prognostic Value of Plasma Big Endothelin-1 in Patients Hospitalized for Heart Failure." Korean Circ J, 2025;55(8):705-717. PMID: 40345830.
- [pubmed] Sun X, et al. "Association between endothelin-1 and diabetic retinopathy: a systematic review and meta-analysis." Front Endocrinol (Lausanne), 2026;17:1754896. PMID: 41847451.
- [pubmed] Lampsas S, et al. "Endothelin-1 Plasma and Aqueous Humor Levels in Different Types of Glaucoma: A Systematic Review and Meta-Analysis." Medicina (Kaunas), 2024;60(7). PMID: 39064546.
- [pubmed] Mangoni AA, et al. "Endothelin-1 as a Candidate Biomarker of Systemic Sclerosis: A GRADE-Assessed Systematic Review and Meta-Analysis With Meta-Regression." Biomark Insights, 2025;20:11772719251318555. PMID: 39990053.
- [pubmed] Murat M, et al. "Serum Endothelin-1 in Suspected Acute Pulmonary Embolism: A Prospective Study." J Cardiovasc Dev Dis, 2026;13(9). PMID: 42783055.
- [pubmed] Gonsalves AM, et al. "Effect of endothelin-1 on the blood pressure response to acute hypoxia and hyperoxia in healthy young men." Physiol Rep, 2024;12(17):e70004. PMID: 39218615.
- [pubmed] Nasci VL, et al. "Sodium intake and biological sex influence urinary endothelin-1 in salt-resistant adults: a pilot study." Am J Physiol Regul Integr Comp Physiol, 2025;329(3):R487-R494. PMID: 40828571.
- [pubmed] Feenstra RGT, et al. "Efficacy and safety of the endothelin-1 receptor antagonist macitentan in epicardial and microvascular vasospasm; a proof-of-concept study." Int J Cardiol Heart Vasc, 2023;47:101238. PMID: 37576078.
- [pubmed] Xu J, et al. "Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential." Drug Discov Today, 2023;28(11):103788. PMID: 37742911.
Sources & Citations
Studies were read from their PubMed abstracts; aprocitentan's US label from DailyMed (SPL dated August 20, 2026). Read October 7, 2026.
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