Dual Endothelin Receptor Antagonists: A New Frontier in Resistant Hypertension

The endothelin pathway represents a significant breakthrough in understanding and treating resistant hypertension through targeted receptor antagonism. Endothelin functions as a powerful vasoconstrictor that causes arterial narrowing and subsequent blood pressure elevation, making it an ideal therapeutic target for patients who don’t respond to conventional treatments. While endothelin-mediated vasoconstriction serves important physiological functions such as bleeding control during injury, excessive activation can contribute to pathological blood pressure elevation in everyday situations.

Aprocitentan represents a dual endothelin receptor antagonist that blocks both endothelin A and endothelin B receptors, distinguishing it from single-receptor antagonists used in pulmonary arterial hypertension treatment. The PRECISION trial, published in The Lancet, demonstrated significant blood pressure reductions when aprocitentan was added to existing 3-drug regimens in patients with confirmed resistant hypertension. This landmark study established the medication’s role in systemic hypertension treatment while differentiating its mechanism from pulmonary hypertension therapies.

The clinical significance of endothelin receptor antagonism extends beyond simple blood pressure reduction to meaningful cardiovascular risk reduction. Dr Cohen emphasizes that every 5 mm Hg reduction in blood pressure corresponds to approximately 10% reduction in adverse cardiovascular outcomes, making the substantial pressure reductions achieved with aprocitentan clinically meaningful. This relationship between blood pressure reduction and cardiovascular protection provides strong rationale for advancing to endothelin receptor antagonist therapy in patients with genuine treatment-resistant hypertension.