Abstract

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially in low-renin conditions, and in hypertensive patients. We investigated the pharmacology of aprocitentan (ACT-132577), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: DOCA-Salt rats (low-renin model) and spontaneously hypertensive rats (SHR, normal renin model). We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHR. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose-dependently decreased BP (statistically significant) and renal vascular resistance and reduced left ventricle hypertrophy (non-significant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHR while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach in hypertension especially with low-renin characteristics and could be used in combination with RAS blockers, without increasing the risk of renal impairment.