https://orcid.org/0000-0002-7979-7758
Hypertension is a major modifiable cardiovascular risk factor and a leading cause of cardiovascular disease and premature death worldwide.1 However, 10–20% of hypertensives present resistant hypertension (RH), defined as blood pressure (BP) levels above the goal despite the concurrent administration of three antihypertensives from distinct classes, including a diuretic, at optimal doses. RH is associated with increased risk for target organ damage and cardiovascular morbidity, and mortality.2
The endothelin system is activated in low-renin and salt-sensitive forms of hypertension, which are common features in patients with RH, but it is not targeted by current antihypertensive drugs.3 Indeed, endothelin-1 (ET-1) is a potent vasoconstrictor and produces endothelial dysfunction, aldosterone and catecholamine release, vascular remodelling, and end-organ damage.4 Canonical signalling pathways activated by ET-1 in vascular smooth muscle and endothelial cells are summarized in Figure 1. Thus, it was hypothesized that RH may be dependent, in part at least, on ET-1. If so, the blockade of the endothelin pathway with a dual endothelin receptor antagonist (ERA) might represent a novel approach to reduce BP in individuals with RH.
![(A) Canonical signalling pathways activated by endothelin-1 (ET-1) in vascular smooth muscle (VSMC) and endothelial cells (EC) and mechanism of action of aprocitentan. ET-1 synthesized in EC from precursors via endothelin converting enzymes (ECE) is released in response to a variety of stimuli and binds to two membrane G-protein (Gp) coupled receptors, ETA and ETB. ET-1 binding to ETA and ETB receptors located on VSMC activates phospholipase C (PLCβ), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds its receptor located on the endoplasmic reticulum (ER) and increases the release of Ca2+ via IP3-sensitive channels into the cytosol and the [Ca2+]i producing a potent vasoconstriction. DAG opens receptor-operated Ca2+ channels (ROC) which further increase the [Ca2+]i and activates myosin light chain kinase (MLCK); both effects also contribute to ET-1-induced vasoconstriction. DAG also activates protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) pathways leading to proliferative effects, vascular remodelling and end-organ damage. Additionally, PKC phosphorylates MLCK promoting actin—myosin cross-bridging and VSMC contraction. Conversely, activation of ETB receptors in EC increases the synthesis of nitric oxide (NO) and prostacyclin (PGI2), and the activation of cyclic adenosine monophosphate(cAMP)/protein kinase A (PKA) and soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathways, respectively, leading to vasodilation. (B) Phase 2 and 3 clinical trials with aprocitentan. Abbreviations. CKD, chronic kidney disease; DB, double-blind; DBP, diastolic blood pressure; DD, double-dummy; EH, essential hypertension; eGFR, estimated glomerular filtration rate; ETAR/ETBR, ETA and ETB receptors; FU, follow-up; HF, heart failure; IL-1, interleukin 1; NCT, ClinicalTrials.gov identifier. od, once daily; PC, placebo-controlled; R, randomized; RH, resistant hypertension; SB, single-blind; SBP, systolic blood pressure; TGF, transforming growth factor; and UCAR, urine albumin-creatinine ratio.](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/ehjcvp/10/5/10.1093_ehjcvp_pvae035/1/m_pvae035fig1.jpeg?Expires=1747861676&Signature=ZVUk9IoUFr2qG-Qlmbx81YcfLbCOKpHeyGCx7-7LwjgpUUiXTKGuKARWkrVeSjxyo9Hyz5ihlZTUikzlsWLZqMgtdueZOzMqni-cL3yMUhTSr3wJVgBGBAUDLOIyjZWcrVw~UgoxeTU8CBW~QzrmQakOS7pM~YlJJkLLS4hXsZzhvZPkAMtqCIyUiTaj8xe2evvKNHMfNFBe8LzRu3HDO3EPcSkaciD0Sl-acWcv~OO5GppStvjVs~L-6MsGg1RVFtU0BmaIWzf5jnwBNt7Nmrn3hgXO9SFYpghqcRlEannEXHoSvxy-FTSY5ifgQdswJcciCLxwF7o6Rym6Q-IaFA__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
(A) Canonical signalling pathways activated by endothelin-1 (ET-1) in vascular smooth muscle (VSMC) and endothelial cells (EC) and mechanism of action of aprocitentan. ET-1 synthesized in EC from precursors via endothelin converting enzymes (ECE) is released in response to a variety of stimuli and binds to two membrane G-protein (Gp) coupled receptors, ETA and ETB. ET-1 binding to ETA and ETB receptors located on VSMC activates phospholipase C (PLCβ), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds its receptor located on the endoplasmic reticulum (ER) and increases the release of Ca2+ via IP3-sensitive channels into the cytosol and the [Ca2+]i producing a potent vasoconstriction. DAG opens receptor-operated Ca2+ channels (ROC) which further increase the [Ca2+]i and activates myosin light chain kinase (MLCK); both effects also contribute to ET-1-induced vasoconstriction. DAG also activates protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) pathways leading to proliferative effects, vascular remodelling and end-organ damage. Additionally, PKC phosphorylates MLCK promoting actin—myosin cross-bridging and VSMC contraction. Conversely, activation of ETB receptors in EC increases the synthesis of nitric oxide (NO) and prostacyclin (PGI2), and the activation of cyclic adenosine monophosphate(cAMP)/protein kinase A (PKA) and soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathways, respectively, leading to vasodilation. (B) Phase 2 and 3 clinical trials with aprocitentan. Abbreviations. CKD, chronic kidney disease; DB, double-blind; DBP, diastolic blood pressure; DD, double-dummy; EH, essential hypertension; eGFR, estimated glomerular filtration rate; ETAR/ETBR, ETA and ETB receptors; FU, follow-up; HF, heart failure; IL-1, interleukin 1; NCT, ClinicalTrials.gov identifier. od, once daily; PC, placebo-controlled; R, randomized; RH, resistant hypertension; SB, single-blind; SBP, systolic blood pressure; TGF, transforming growth factor; and UCAR, urine albumin-creatinine ratio.
In both animal models and hypertensive patients, ERAs decrease BP and prevent end-organ damage3 but many clinical programs were discontinued by safety concerns related to fluid retention/edema, and hepatotoxicity. Thus, no ERA has been approved for the treatment of arterial hypertension, and only one ERA, aprocitentan, was developed for the treatment of RH.
Aprocitentan, the active metabolite of macitentan, is a once-daily, orally active, dual ERA that potently inhibits the binding of ET-1 to ETA and ETB receptors (ETA/ETB inhibitory potency ratio 1:16).3,4 It is rapidly absorbed reaching peak plasma levels within 3–9 h, is highly bound to plasma proteins (>99%), presents a volume of distribution of 40 L, is metabolized independently from CYP450 enzymes and presents a half-life of 44 h.4 No dose adjustment is required in patients with moderate hepatic or severe renal impairment and can be administered with cytochrome P450 inhibitors/inducers. The mechanism of action and main clinical trials with aprocitentan are shown in Figure 1.
In a phase 2 dose-finding study in patients with essential hypertension, aprocitentan (5–50 mg) decreased sitting systolic/diastolic BP (SBP/DBP) in a dose‐dependent manner with a maximal reduction at 25 mg od (9.9/7.0 mgHg), while lisinopril (20 mg od) decreased SBP/DBP by 4.8/3.8 mmHg compared with placebo.5 The phase 3 PRECISION trial, analysed the long-term efficacy and safety of aprocitentan (12.5 and 25 mg) with both office and ambulatory BP measurements in patients with RH using a unique design.6 After 4 weeks of treatment, the least square mean (SE) change in office SBP with both doses of aprocitentan was −3.7 (1.3) mmHg (P = 0.0042) compared with placebo. The respective difference for 24‐h ambulatory SBP was −4.2 mm Hg and −5.9 mm Hg, respectively. The SBP/DBP reduction was maintained for 44 weeks. Following 4 weeks of withdrawal, office SBP significantly increased with placebo compared with aprocitentan.
The most common adverse effect of aprocitentan was mild‐moderate oedema/fluid retention. In the PRECISION trial,6 oedema/fluid retention occurred in 9.1%, 18.4%, and 2.1% of patients treated with aprocitentan 12.5 or 25 mg or placebo during the step 1 and in 18.2% of patients receiving aprocitentan 25 mg during 32-weeks. Oedema/fluid retention was more frequent in patients with chronic kidney disease stage 3–4 and, possibly, with underlying left ventricular dysfunction. Hepatic disorders were observed in 2.3% of patients treated with aprocitentan 25 mg. Aprocitentan may cause embryo-foetal harm if used during pregnancy.
Based on these results, and after 30 years of clinical research, aprocitentan is the first ERA approved in combination with other drugs for the treatment of patients with RH.
Conflict of interest: None.
Data availability
There are no new data associated with this article.
