Endothelin-1 Receptor Subtypes
Vascular Smooth Muscle
ETA Receptor
- Vasoconstriction (sustained)
- Smooth muscle proliferation
- Vascular remodeling and fibrosis
- Primary driver of pulmonary arterial hypertension pathology
- Blocked by all three endothelin receptor antagonists
Endothelium + Smooth Muscle
ETB Receptor
- Endothelial ETB: vasodilation via nitric oxide and prostacyclin
- Smooth muscle ETB: vasoconstriction
- Clears endothelin-1 from circulation
- Blocked by bosentan and macitentan (dual antagonists)
- Preserved by ambrisentan (selective ETA only)
Endothelin Receptor Antagonist Comparison
| Feature |
Selectivity |
Bosentan |
Ambrisentan |
Macitentan |
| Receptor target |
|
Dual ETA + ETB |
Selective ETA |
Dual ETA + ETB |
| Hepatotoxicity |
|
High (~10%) — monthly LFTs |
Low |
Low |
| CYP induction |
|
Yes — many interactions |
No |
No |
| Key interaction |
|
Cyclosporine contraindicated; reduces warfarin, hormonal contraceptives |
Minimal |
Minimal |
| Edema risk |
|
Moderate |
Higher |
Moderate |
| Anemia risk |
|
Low |
Low |
Yes — monitor hemoglobin |
| Key trial |
|
BREATHE-1 |
ARIES-1, ARIES-2 |
SERAPHIN (45% reduction morbidity/mortality) |
Class Safety Rules — All Endothelin Receptor Antagonists
| Rule | Detail |
|---|
| Contraindicated in pregnancy |
Teratogenic in animals at sub-therapeutic doses — fetal cardiovascular and craniofacial malformations |
| Mandatory contraception |
Two reliable methods simultaneously; bosentan requires non-hormonal methods (reduces hormonal contraceptive levels) |
| Monthly pregnancy test |
Required for all women of childbearing potential throughout treatment |
| Bosentan: monthly LFTs |
Stop or reduce dose if transaminases exceed 3× upper limit of normal — reversible on discontinuation |
| Combine with PDE5 inhibitor |
Sildenafil or tadalafil added to endothelin receptor antagonist is current guideline-recommended combination for pulmonary arterial hypertension |