Endothelin-1

What is Endothelin-1?

Endothelin-1 (ET-1) is a 21-amino-acid endogenous peptide secreted predominantly by vascular endothelial cells and is the most potent vasoconstrictor identified in mammalian biology — orders of magnitude more potent on a molar basis than angiotensin II or norepinephrine. It was isolated, sequenced, and named in 1988 by Masashi Yanagisawa, Tomoh Masaki, and colleagues at the University of Tsukuba, who purified it from the conditioned medium of cultured porcine aortic endothelial cells and reported the structure in Nature. The molecule is unusual in two respects: it contains two intramolecular disulfide bonds that lock it into a rigid bicyclic conformation (Cys1-Cys15 and Cys3-Cys11), and it is generated through a two-step proteolytic maturation in which a 212-residue preproendothelin-1 precursor is first cleaved by furin to a 38-residue intermediate called big endothelin-1, then cleaved by endothelin-converting enzyme (ECE-1, a membrane-bound zinc metalloprotease characterized by Xu and colleagues in 1994) to release the mature 21-residue active peptide. ET-1 is one of three closely related endothelin isoforms (ET-1, ET-2, ET-3), with ET-1 the dominant cardiovascular isoform. It signals through two G-protein-coupled receptors, ETA and ETB, cloned in parallel by Arai and Sakurai laboratories in 1990. ETA receptors on vascular smooth muscle mediate vasoconstriction and proliferation. ETB receptors on endothelial cells mediate vasodilation through release of nitric oxide and prostacyclin and also act as a clearance receptor that removes circulating ET-1 from the bloodstream. The system is implicated in pulmonary arterial hypertension, systemic and resistant hypertension, chronic kidney disease, heart failure, scleroderma, and a range of other vascular pathologies — and the endothelin receptor antagonist (ERA) drug class targeting these receptors has produced four FDA-approved drugs (bosentan, ambrisentan, macitentan, aprocitentan).

What Endothelin-1 Is Investigated For

Endothelin-1 is not a peptide that consumers take. It is an endogenous vasoactive peptide and one of the most successful drug-target stories in modern cardiovascular pharmacology. The relevance to a peptide reader is the receptor antagonist class — endothelin receptor antagonists (ERAs) — that grew out of the basic biology. Bosentan (Tracleer, dual ETA/ETB) was the first ERA approved by the FDA, in 2001, on the strength of the BREATHE-1 randomized trial (Rubin et al. 2002 NEJM) showing improved six-minute walk distance in pulmonary arterial hypertension. Ambrisentan (Letairis, ETA-selective) followed in 2007 based on the ARIES-1 and ARIES-2 trials. Macitentan (Opsumit, dual) was approved in 2013 on the back of the SERAPHIN long-term outcomes trial — the first PAH trial to demonstrate a morbidity-mortality benefit rather than a functional surrogate. Aprocitentan (Tryvio, dual) was approved in March 2024 for treatment-resistant hypertension based on the PRECISION trial (Schlaich et al. 2022 Lancet). Beyond pulmonary hypertension and resistant hypertension, ET-1 biology has been investigated in chronic kidney disease (the SONAR trial of atrasentan in diabetic kidney disease showed renal benefit but never reached approval), heart failure (multiple ERA trials in heart failure with reduced ejection fraction were neutral or negative), scleroderma-associated digital ulcers (bosentan is approved in some jurisdictions for this indication), and a range of vascular and fibrotic conditions. The honest framing is that endothelin-1 itself is not a therapeutic peptide and never will be — what matters clinically is the receptor pharmacology that emerged from understanding it.

History & Discovery

The endothelin story began in the early 1980s with observations from Robert Furchgott and others that vascular endothelium produced not only relaxing factors (later identified as nitric oxide) but also a constricting factor — designated endothelium-derived constricting factor or EDCF. The molecular identity of this factor was resolved in 1988 when Masashi Yanagisawa, Hiroki Kurihara, Sadao Kimura, Tomoaki Tomobe, Mariko Kobayashi, Yuzuru Mitsui, Yoshio Yazaki, Katsutoshi Goto, and Tomoh Masaki at the University of Tsukuba isolated, sequenced, and synthesized a 21-amino-acid peptide from porcine aortic endothelial cell conditioned medium and reported it in Nature. They named it 'endothelin' for its endothelial origin. The discovery paper showed extraordinary vasoconstrictor potency in isolated artery preparations and structural features — two intramolecular disulfide bridges and a hydrophobic C-terminal tail — that distinguished it from any previously known vasoactive peptide. The receptor pharmacology was established within two years. In December 1990, two back-to-back Nature papers from Japanese groups cloned the two endothelin receptor subtypes: Arai, Hori, Aramori, Ohkubo, and Nakanishi reported the first cloned endothelin receptor (ETA, isopeptide-selective for ET-1 and ET-2 over ET-3), and Sakurai, Yanagisawa, Takuwa, Miyazaki, Kimura, Goto, and Masaki reported a non-isopeptide-selective subtype (ETB, equal affinity for ET-1, ET-2, and ET-3). These two papers established the ETA/ETB framework that has organized the field ever since. The biosynthetic pathway was completed in 1994 when Xu, D'Orleans-Juste, Yanagisawa, and colleagues characterized endothelin-converting enzyme (ECE-1) in Cell, identifying the membrane-bound metalloprotease that cleaves big endothelin-1 to the active 21-residue peptide. The pathophysiologic and therapeutic translation moved with unusual speed for a vasoactive-peptide field. Stewart, Levy, Cernacek, and Langleben reported elevated plasma endothelin-1 in pulmonary hypertension in their 1991 Annals of Internal Medicine paper, framing the marker-versus-mediator question that the receptor-antagonist trials would later resolve. Hoffmann-La Roche / Actelion (founded by Martine Clozel and colleagues to develop endothelin antagonists after Roche divested the program) brought bosentan through development. Channick and colleagues' 2001 Lancet paper reported the first randomized placebo-controlled bosentan trial in pulmonary hypertension, and the larger BREATHE-1 trial (Rubin et al., NEJM 2002) supported FDA approval the same year. Ambrisentan (ARIES-1/2, Galie et al., Circulation 2008) and macitentan (SERAPHIN, Pulido et al., NEJM 2013) followed for PAH. The SONAR trial (Heerspink et al., Lancet 2019) established atrasentan's renal benefit in diabetic kidney disease. The PRECISION trial of aprocitentan (Schlaich et al., Lancet 2022) supported FDA approval in March 2024 for treatment-resistant hypertension — the first new mechanism for that indication in many years and the most recent major regulatory milestone for the endothelin antagonist class. By 2026, four ERAs are FDA-approved, the 2022 ESC/ERS pulmonary hypertension guidelines establish ERAs as a foundational PAH therapy, and ET-1 remains one of the most thoroughly translated peptide targets in modern cardiovascular medicine.

How It Works

Your blood vessels are lined with a thin layer of cells called the endothelium. These cells release endothelin-1, a small peptide that tells the muscle wrapped around each blood vessel to squeeze. Endothelin-1 is the strongest blood-vessel-tightening signal in the human body — much stronger than adrenaline or angiotensin. It works through two locks (receptors) named ETA and ETB. ETA receptors on the muscle cells cause squeezing. ETB receptors on the endothelium itself cause the opposite — relaxation — and also vacuum endothelin-1 out of the blood. Too much endothelin-1 contributes to high blood pressure in the lungs (pulmonary hypertension) and several other vascular diseases. Drugs that block the endothelin receptors — bosentan, ambrisentan, macitentan, and aprocitentan — are FDA-approved to treat pulmonary arterial hypertension and, as of 2024, treatment-resistant high blood pressure.

Endothelin-1 is encoded by the EDN1 gene as a 212-amino-acid preproendothelin-1 precursor. Furin cleaves the precursor to a 38-residue intermediate (big endothelin-1), which is then cleaved by endothelin-converting enzyme (ECE-1, a membrane-bound zinc metalloprotease characterized by Xu, D'Orleans-Juste, Yanagisawa, and colleagues in their 1994 Cell paper) at a Trp21-Val22 bond to release the mature 21-amino-acid peptide. The mature peptide contains two intramolecular disulfide bridges (Cys1-Cys15 and Cys3-Cys11) that constrain it into a bicyclic conformation with an extended C-terminal tail required for receptor binding. ET-1 is the dominant cardiovascular isoform of a three-member endothelin family (ET-1, ET-2, ET-3), each encoded by a distinct gene with overlapping but partially distinct tissue distributions. ET-1 signals through two G-protein-coupled receptors of the rhodopsin family, both cloned in 1990. ETA (encoded by EDNRA), reported by Arai, Hori, Aramori, Ohkubo, and Nakanishi in Nature, is highly selective for ET-1 and ET-2 over ET-3 and is densely expressed on vascular smooth muscle cells, cardiomyocytes, and a range of other cell types. ETA couples primarily to Gq/11, activating phospholipase C, mobilizing intracellular calcium, and producing sustained vasoconstriction and pro-mitogenic signaling on smooth muscle. ETB (encoded by EDNRB), reported by Sakurai, Yanagisawa, Takuwa, Miyazaki, Kimura, Goto, and Masaki in the same December 1990 issue of Nature, has equal affinity for all three endothelin isoforms and is expressed predominantly on vascular endothelial cells, with additional expression on smooth muscle in some vascular beds. ETB couples to both Gq/11 and Gi/o and produces release of nitric oxide and prostacyclin from endothelium — a vasodilator action that opposes ETA-mediated constriction. ETB also functions as a 'clearance receptor' that internalizes circulating ET-1 and is the principal mechanism for plasma ET-1 clearance, particularly in the pulmonary circulation. Loss-of-function mutations in EDNRB and the gene encoding ET-3 (EDN3) cause Hirschsprung disease type 4 and Waardenburg-Shah syndrome through impaired migration of enteric neural crest cells and melanocytes, illustrating that the endothelin system has roles beyond cardiovascular tone. In pulmonary arterial hypertension, ET-1 production is increased in the pulmonary vasculature, ETA-mediated vasoconstriction and smooth-muscle proliferation contribute to the obliterative remodeling that characterizes the disease, and ETB-mediated clearance is impaired. Endothelin receptor antagonists (ERAs) block this signaling at the receptor level. Selective ETA antagonists (ambrisentan) preserve ETB-mediated vasodilation and clearance; dual ETA/ETB antagonists (bosentan, macitentan, aprocitentan) block both arms. The clinical evidence in PAH is most developed for dual antagonism — macitentan in the SERAPHIN trial demonstrated a composite morbidity-mortality benefit that ambrisentan and bosentan trials, designed around six-minute walk distance, were not powered to capture. In treatment-resistant hypertension, the PRECISION trial of aprocitentan demonstrated sustained blood pressure reductions on top of optimized triple therapy, leading to FDA approval in March 2024 — the first novel mechanism for resistant hypertension in many years.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Endothelin-1:

• 01Whether selective ETA antagonism is meaningfully superior, inferior, or equivalent to dual ETA/ETB antagonism in pulmonary arterial hypertension long-term outcomes — three decades of pharmacology has not resolved the debate, and head-to-head trials are unlikely.
• 02Whether endothelin receptor antagonists provide durable renal benefit in chronic kidney disease beyond what was shown in SONAR — and whether the regulatory failure of atrasentan in diabetic nephropathy reflects a real ceiling on the strategy or a strategic-development decision.
• 03Whether ERAs benefit patients with heart failure with preserved ejection fraction (HFpEF) or with combined pre- and post-capillary pulmonary hypertension — earlier ERA trials in HFrEF were neutral or negative, but the HFpEF question remains open.
• 04Whether endothelin receptor antagonism has a role in chronic thromboembolic pulmonary hypertension (CTEPH) beyond the established place of macitentan in inoperable disease.
• 05Whether targeting ECE-1 or the ET-1 production pathway upstream offers therapeutic advantage over receptor antagonism — small-molecule ECE inhibitors have been developed but have not advanced clinically.
• 06The role of endothelin signaling in cancer biology — particularly the ETA receptor in prostate, ovarian, and colorectal cancers — where preclinical data have been promising but trials of zibotentan and atrasentan in oncology have been unsuccessful.
• 07Whether biomarker-guided patient selection (plasma ET-1, big ET-1, ECE-1 expression) can identify ERA responders more precisely than current clinical criteria.
• 08The contribution of endothelin signaling to neurovascular disease — including subarachnoid hemorrhage vasospasm, where the clazosentan story showed receptor-antagonism activity on angiographic vasospasm without clear clinical-outcome benefit.

Forms & Administration

Endothelin-1 itself is not formulated or approved as a therapeutic in any jurisdiction. Synthetic ET-1 is produced as a research reagent for use in receptor binding assays, isolated tissue pharmacology, and controlled human and animal infusion studies under research protocols. The clinically relevant forms are the four FDA-approved endothelin receptor antagonists (oral tablets): bosentan (Tracleer, 62.5-125 mg twice daily), ambrisentan (Letairis, 5-10 mg once daily), macitentan (Opsumit, 10 mg once daily), and aprocitentan (Tryvio, 12.5 mg once daily). All require prescription, specialist diagnosis (PAH or resistant hypertension), and (for the PAH agents) participation in REMS programs designed around hepatotoxicity and teratogenicity monitoring. ET-1 sold through peptide-marketplace channels has no validated therapeutic application and would pose acute cardiovascular risk if administered.

Common Questions

Who Endothelin-1 Is NOT For

Drug & Supplement Interactions

Endothelin-1 itself has no clinical drug-interaction profile because it is not therapeutically administered. The endothelin receptor antagonist class has well-characterized interactions, predominantly through CYP2C9 and CYP3A4 metabolism. Bosentan is the most interaction-prone of the class: it is both a substrate and an inducer of CYP3A4 and CYP2C9, lowering plasma concentrations of co-administered drugs metabolized by these enzymes (including hormonal contraceptives — making bosentan-treated women requiring effective non-hormonal contraception under REMS rules). Bosentan is contraindicated with cyclosporine A (cyclosporine markedly raises bosentan levels) and with glyburide (combined hepatotoxicity risk). Ambrisentan has a comparatively clean interaction profile and is less dependent on CYP-mediated metabolism. Macitentan is metabolized by CYP3A4 to an active metabolite and shows clinically relevant interactions with strong CYP3A4 inhibitors (ketoconazole, ritonavir) and inducers (rifampin). Aprocitentan, the most recently approved ERA, has a relatively low drug-interaction profile per PRECISION-era pharmacokinetic studies. Across the class, additive blood-pressure reduction with other antihypertensives is expected and is the basis of aprocitentan's resistant-hypertension indication. Combined use with PDE5 inhibitors (sildenafil, tadalafil) is common and supported in pulmonary arterial hypertension treatment algorithms.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions