Endothelin Receptor Antagonists

Introduction & the endothelin system

• Endothelin receptor antagonists (ERAs) are orally active, non-peptide, small-molecule competitive antagonists of endothelin receptors that block the vasoconstrictor, mitogenic and profibrotic actions of endothelin-1 (ET-1); the class — bosentan, macitentan and ambrisentan — is a first-line oral pharmacotherapy for pulmonary arterial hypertension (PAH).
• The endothelins — ETs are a trio of 21-amino-acid peptides (ET-1, ET-2, ET-3), each from a different gene, with potent, relatively long-lasting vasoconstrictor activity; ET-1 is the predominant, functionally most relevant isoform, made chiefly by vascular endothelial cells. Each contains two intramolecular disulfide bridges.
• Rationale — In PAH there is a pathological imbalance between vasoconstrictor/mitogenic mediators (ET-1, thromboxane A₂, 5-HT) and vasodilator/antiproliferative mediators (NO, prostacyclin/PGI₂); antagonising ET-1 helps restore that balance, reducing vasoconstriction, vascular remodeling and in situ thrombosis. Plasma ET-1 is raised up to ~10-fold in PAH, correlating with disease severity.
• Scope — The parallel NO/cGMP (sildenafil, riociguat) and prostacyclin (epoprostenol, treprostinil, selexipag) classes are mentioned only as comparators/combination partners, not as primary content.