Endothelin-1

Cardiovascular / Vasoactive

Also known as: ET-1, Endothelin, Preproendothelin-1

EndothelinsResearch phase: Endogenous peptide (well characterized)Regulatory: Endogenous peptide. ET receptor antagonists (bosentan, ambrisentan, macitentan) are FDA-approved for PAH.

Mechanism

Endothelin-1 is the most potent vasoconstrictor known in the human body. This 21-amino-acid peptide is produced by blood vessel lining cells and causes powerful, long-lasting blood vessel constriction. Overproduction of ET-1 contributes to pulmonary arterial hypertension, heart failure, and kidney disease. Drugs that block its receptors (bosentan, ambrisentan) are used to treat PAH.

Technical detail

Endothelin-1 (ET-1) is a 21-amino-acid peptide with two intramolecular disulfide bonds, produced from big-endothelin-1 by endothelin-converting enzyme (ECE-1) in endothelial cells. It binds ETA receptors (Gq-coupled, on vascular smooth muscle) causing potent vasoconstriction via PLC-IP3-Ca2+ signaling and Rho kinase-mediated calcium sensitization, and ETB receptors (on endothelium for NO/prostacyclin release, and on smooth muscle for constriction). ET-1 has a half-life of minutes but receptor-bound duration of action lasting hours. Implicated in PAH pathogenesis, cardiac fibrosis, and renal dysfunction.

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