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 under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (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 SHRs. 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 (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs 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 to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.
Highlights
Endothelin (ET)-1 is a potent vasoconstrictor peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, vascular hypertrophy and remodeling, fibrosis, and endothelial dysfunction (Iglarz and Clozel, 2010)
Plasma renin activity was significantly blunted in deoxycorticosterone acetate (DOCA)-salt rats compared with spontaneously hypertensive rat (SHR) and Wistar rats (Fig. 2A)
The dose-response effects of aprocitentan and the angiotensin II type-1 receptor blocker (ARB) valsartan on maximal Mean arterial pressure (MAP) decrease and area between the curves (ABC) were compared in these models
Summary
Endothelin (ET)-1 is a potent vasoconstrictor peptide that causes neurohormonal and sympathetic activation, increased aldosterone synthesis and secretion, vascular hypertrophy and remodeling, fibrosis, and endothelial dysfunction (Iglarz and Clozel, 2010). ET-1, and probably ET-2 and ET-3, can contribute to the pathogenesis of hypertension and related end-organ damage via their receptors, ETA and ETB. Endothelin receptor antagonists (ERAs) demonstrate greater efficacy in salt-dependent/low-renin animal models of hypertension than in high/normal renin animal models (Schiffrin, 1998a). Aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide) (Fig. 1A) is the active metabolite of macitentan, a dual ETA/ETB ERA, which demonstrated long-term efficacy in pulmonary hypertension. Aprocitentan is a potent, orally active, dual ETA/ETB ERA with an ETA/ETB inhibitory potency ratio of 1:16, as determined by in vitro functional assays (Iglarz et al, 2008), and a long half-life (44 hours) in humans (Sidharta et al, 2018)
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