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Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.

Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamine-independent pruritus. Recently, its involvement in cutaneous inflammation has begun to draw attention. The upregulation of ET-1 expression in the epidermis of human psoriasis patients has been reported. It was also demonstrated that ET-1 can stimulate dendritic cells to induce Th17/1 immune responses. However, the role of the interaction between ET-1 and ET-1 receptors in the pathogenesis of psoriasis remains elusive. Here, we investigated the effects of ET-1 receptor antagonist on imiquimod (IMQ) -induced psoriasiform dermatitis in mouse. Psoriasis-related cytokines such as IL-17A and TNF-α induced ET-1 expression in human keratinocytes. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and also significantly inhibited the histological inflammation and cytokine expression (TNF-α, IL-12p40, IL-12 p19, and IL-17) in the lesional skin of the mouse model. Furthermore, topical application of ambrisentan suppressed phenotypic and functional activation of dendritic cells in lymph nodes. Our findings indicate that the ET-1 and ETAR axis plays an important role in the pathogenesis of psoriasis and is a potential therapeutic target for treating psoriasis.

Aprocitentan is an orally active, dual endothelin (ET) receptor antagonist developed for the treatment of hypertension in which, despite available treatments, a medical need exists for drugs with a new mechanism of action. In this study, the single- and multiple-dose tolerability, safety, pharmacokinetics (PK), and pharmacodynamics of up to 600 mg (single doses) and 100 mg once a day (qd; multiple doses) of aprocitentan were investigated in healthy male and female subjects. The effect of age on the tolerability and PK parameters was investigated at a dose of 100 mg qd. Aprocitentan was well tolerated across all doses. No serious adverse events (AEs) occurred. The most frequently reported AE was headache. Small increases in body weight were recorded in subjects receiving 100 mg qd. Plasma concentration-time profiles of aprocitentan were similar after single- and multiple-dose administration, and support a qd dosing regimen based on a half-life of 44 hours. After multiple doses, PK was dose proportional. Accumulation at steady state, reached by Day 8, was 3-fold. Only minor differences in exposure between healthy females and males, healthy elderly and adult subjects, and fed and fasted conditions were observed. Plasma ET-1 concentrations, reflecting ET receptor antagonism, significantly increased with doses ≥25 mg. Time-matched analysis of electrocardiogram (ECG) parameters did not suggest drug-induced ECG effects. Exposure-response analysis indicated no QTc prolongations at plasma levels up to 10 µg/mL. Aprocitentan was well tolerated in healthy subjects with a PK profile favorable for qd dosing.

Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They are categorized into acute kidney injury and chronic kidney disease. Current preclinical and clinical trials have demonstrated that endothelin (ET) is linked to the onset and progression of kidney disease. In kidney diseases, pathological conditions such as hyperglycemia, acidosis, insulin resistance, and elevated angiotensin II levels lead to an increase in ET. This elevation activates endothelin receptor type A, resulting in harmful effects like proteinuria and a reduced glomerular filtration rate (GFR). Therefore, to slow the progression of kidney disease, endothelin receptor antagonists (ERAs) have been proposed as promising new therapies. Numerous studies have demonstrated the efficacy of ERAs in significantly reducing proteinuria and improving GFR, thereby slowing the progression of kidney diseases. This review discusses the mechanisms of action of ERAs in treating kidney disease, their efficacy and safety in preclinical and clinical studies, and explores future prospects for ERAs.

Chronic kidney disease (CKD) is the main cause of end-stage renal disease worldwide arising as a frequent complication of diabetes, obesity, and hypertension. Current therapeutic options, mainly based of inhibition of the renin-angiotensin system (RAS), provide imperfect renoprotection if started at an advanced phase of the disease, and treatments that show or even reverse the progression of CKD are needed. The endothelin (ET) system contributes to the normal renal physiology; however, robust evidence suggests a key role of ET-1 and its cognate receptors, in the progression of CKD. The effectiveness of ET receptor antagonists in ameliorating renal hemodynamics and fibrosis has been largely demonstrated in different experimental models. A significant antiproteinuric effect of ET receptor antagonists has been found in diabetic and non-diabetic CKD patients even on top of RAS blockade, and emerging evidence from ongoing clinical trials highlights their beneficial effects on a wide range of kidney disorders.

Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a “gatekeeper” for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.

Macitentan (Opsumit ® ) is a novel dual endothelin receptor antagonist (ERA) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd. In October 2013, oral macitentan 10 mg once daily received its first global approval in the US, followed closely by Canada, for the treatment of pulmonary arterial hypertension (PAH). The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH, and is under regulatory review in several other countries for the same indication. Endothelin (ET)-1 influences pathological changes via two ET receptor subtypes (ET A and ET B ), to which it binds with high affinity. ET-1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH. Clinical development is underway for other indications, including Eisenmenger syndrome, ischaemic digital ulcers secondary to systemic sclerosis, and glioblastoma. Macitentan was also evaluated in idiopathic pulmonary fibrosis; however, a phase 2 trial did not meet its primary endpoint and further investigation in this indication was discontinued. Macitentan was developed by modifying the structure of bosentan in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs. This article summarizes the milestones in the development of macitentan leading to this first approval for PAH.

The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ETA and ETB), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes.

We hypothesized that chronic specific endothelin-A (ET-A) receptor blockade therapy would reverse renal dysfunction and injury in advanced experimental renovascular disease. To test this, unilateral renovascular disease was induced in 19 pigs, and after 6 weeks, single-kidney hemodynamics and function was quantified in vivo using computed tomography. All pigs with renovascular disease were divided such that seven were untreated, seven were treated with ET-A blockers, and five were treated with ET-B blockers. Four weeks later, all pigs were restudied in vivo, and then killed and ex vivo studies performed on the stenotic kidney to quantify microvascular density, remodeling, renal oxidative stress, inflammation, and fibrosis. Renal blood flow, glomerular filtration rate, and redox status were significantly improved in the stenotic kidney after ET-A but not ET-B blockade. Furthermore, only ET-A blockade therapy reversed renal microvascular rarefaction and diminished remodeling, which was accompanied by a marked decreased in renal inflammatory and fibrogenic activity. Thus, ET-A but not ET-B blockade ameliorated renal injury in pigs with advanced renovascular disease by stimulating microvascular proliferation and decreasing the progression of microvascular remodeling, renal inflammation, and fibrosis in the stenotic kidney. These effects were functionally consequential as ET-A blockade improved single kidney microvascular endothelial function, renal blood flow, and glomerular filtration rate, and decreased albuminuria.

Pulmonary arterial hypertension is a progressive, debilitating disease caused by a dysregulation of the pulmonary vascular tone that inevitably leads to right heart failure and death without treatment. Until relatively recently, the treatment options for those afflicted by pulmonary arterial hypertension were limited; today, a greater understanding of the pathophysiology behind this disease has led to several evidence-based therapies that can improve pulmonary function and quality of life for these patients. One of the primary mediators of pulmonary vascular tone is endothelin-1, which is a potent and long-lasting vasoconstrictor. Macitentan is a second-generation endothelin receptor antagonist that acts selectively as a pulmonary vasodilator without the significant side effects noted with previous endothelin receptor antagonists. This review focuses on the mechanism of action and pharmacokinetics of macitentan, as well as the adverse effects, efficacy, and clinical uses of macitentan in the clinical trials to date. In addition, the authors briefly review clinical trials currently underway to illustrate possible future directions for the use of macitentan.