endothelin-1

**Synthesis:** Preproendothelin-1 is cleaved to big endothelin-1, which endothelin-converting enzyme (ECE) converts to active ET-1 (21 amino acids, two disulfide bonds). It is produced mainly by vascular endothelial cells. Stimuli for release include angiotensin II, hypoxia, shear stress, thrombin, TGF-β, insulin, and catecholamines. Stimuli that inhibit release include NO, prostacyclin (PGI2), and ANP.

**Receptors (both GPCRs):** - **ET-A** is on vascular smooth muscle. It is Gq-coupled, so it increases PLC, IP3, and intracellular Ca²⁺. This causes sustained, potent vasoconstriction, smooth muscle proliferation, and hypertrophy/fibrosis. - **ET-B** is on endothelial cells and smooth muscle. On endothelium it causes vasodilation (via NO and PGI2 release) and clears circulating ET-1, especially in the lung. On smooth muscle it causes vasoconstriction.

**Physiologic and pathologic roles:** - It maintains vascular tone and has a long duration of action. - It is a key mediator in pulmonary arterial hypertension (PAH), where levels are elevated and correlate with disease severity. - It contributes to systemic hypertension (especially salt-sensitive and resistant), heart failure, and renal disease (it reduces GFR and promotes proteinuria and fibrosis). - It contributes to cerebral vasospasm after subarachnoid hemorrhage. - It is elevated in atherosclerosis, scleroderma-associated digital ischemia and digital ulcers, and Raynaud phenomenon. - Its levels are increased in preeclampsia. - Endothelial dysfunction (e.g., in diabetes, hyperlipidemia) shifts the balance toward ET-1 and away from NO.

**Pharmacology (endothelin receptor antagonists, ERAs):** - **Bosentan** is a dual ET-A/ET-B antagonist. Adverse effects are hepatotoxicity (monitor LFTs), teratogenicity, and decreased efficacy of hormonal contraceptives (CYP3A4 inducer). - **Ambrisentan** is ET-A selective. Its main adverse effects are teratogenicity and peripheral edema. - **Macitentan** is a dual antagonist. - **Class effects:** Teratogenicity (contraindicated in pregnancy; REMS program), peripheral edema, anemia, and testicular atrophy/decreased fertility. - **Other PAH drug classes:** PDE-5 inhibitors (sildenafil, tadalafil), prostacyclin analogs (epoprostenol, treprostinil), and soluble guanylate cyclase stimulators (riociguat). - **Sparsentan** is a dual ET-A/angiotensin II receptor antagonist used in IgA nephropathy.

**Board pearls:** - ET-1 is the most potent vasoconstrictor known, and its effect is opposed by NO, PGI2, and ANP. - In PAH, ERAs block vasoconstriction and vascular remodeling. - Mnemonic: ERAs end in **-sentan**. - Teratogenicity is the major class warning.