Endothelin Antagonism: A New Era for Resistant Hypertension?

Hypertension is a major global health burden and a leading contributor to cardiovascular disease and chronic kidney disease (CKD). Despite the availability of multiple antihypertensive therapies, blood pressure control remains suboptimal, and a significant proportion of patients develop resistant hypertension, defined as uncontrolled blood pressure despite treatment with three or more agents including a diuretic. These individuals are at particularly high risk of adverse cardiovascular and renal outcomes, highlighting an unmet need for novel therapeutic strategies. Endothelin-1 (ET-1), the most potent endogenous vasoconstrictor, plays a key role in the regulation of vascular tone, sodium balance and renal function. Dysregulation of the endothelin system has been implicated in the pathophysiology of resistant hypertension through its interactions with the renin-angiotensin-aldosterone system, sympathetic nervous system activation and endothelial dysfunction. Early studies of endothelin receptor antagonists (ERAs) in hypertension were limited by adverse effects, particularly fluid retention. However, the development of newer agents has renewed interest in this pathway. In the phase 3 PRECISION trial, aprocitentan significantly reduced blood pressure in patients with resistant hypertension, with additional reductions in albuminuria. Endothelin antagonism represents a promising therapeutic approach in resistant hypertension, particularly in patients with CKD, and may provide benefits beyond blood pressure reduction.