Therapeutic Targeting of Endothelin Receptors

The discovery of endothelin’s role in PAH led to the development of endothelin receptor antagonists (ERAs), now a cornerstone of therapy.

• Selective ETA antagonists (e.g., ambrisentan) block the pathological vasoconstriction and smooth muscle proliferation mediated by ETA receptors while preserving protective ETB functions.
• Dual ETA/ETB antagonists (e.g., bosentan, macitentan) offer broader suppression of endothelin signaling but may interfere with ETB-mediated vasodilation and clearance.

Clinical trials have shown that ERAs improve exercise capacity, pulmonary hemodynamics, and time to clinical worsening in PAH patients. Combination therapy with phosphodiesterase-5 inhibitors or prostacyclin analogs further enhances therapeutic outcomes.