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Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline‐recommended therapy. While spironolactone is widely considered as the preferable fourth‐line drug, its broad application is limited by its side effect profile, especially off‐target steroid receptor‐mediated effects and hyperkalaemia in at‐risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter‐based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension. [ABSTRACT FROM AUTHOR]

With chronic kidney disease (CKD) being a global arising health problem, strategies for delaying kidney disease progression and reducing the high cardiovascular risk inherent to CKD, are the main objectives of the actual management of patients with kidney diseases. In these patients, the control of arterial hypertension is essential, as high blood pressure (BP) is a strong determinant of worst cardiovascular and renal outcomes. Achieving target blood pressures recommended by international guidelines is mandatory and often demands a multiple levels management, including several pharmacological and lifestyle measures. Even in the presence of adequate BP control, the residual cardiovascular risk remains high. In this respect, the recent demonstration that novel agents such as sodium glucose transporter 2 (SGLT2) inhibitors or the new non-steroidal mineralocorticoid antagonist finerenone can retard the progression of kidney diseases and reduce cardiovascular mortality on top of standard of care treatment with renin-angiotensin system inhibitors represent enormous progresses. These studies also demonstrate that cardiovascular and renal protection can be obtained beyond blood pressure control. Other promising novelties are still to come such as renal denervation and endothelin receptor antagonists in the setting of diabetic and non-diabetic kidney diseases. In the present review, we shall discuss the classic and the new aspects for the management of hypertension in CKD, integrating the new data from recent clinical studies. [ABSTRACT FROM AUTHOR]

Background: There are currently three Food and Drug Administration approved endothelin receptor antagonists (ERAs): bosentan, ambrisentan, and macitentan. There is a growing body of evidence that demonstrates the beneficial effects of ERAs in patients with pulmonary arterial hypertension (PAH). Objectives: To compare the available evidence from randomized clinical trials for specific outcomes of different endothelin antagonists for the treatment of PAH. Methods: A multi-database search of randomized controlled trials up to March 15, 2016 was conducted for those that would measure functional parameters of patients with PAH treated with ERA monotherapy versus placebo. Studies that analyzed 6-min walking distance, pulmonary vascular resistance, pulmonary arterial pressure, or WHO functional status were incorporated for analysis. A total of 15 trials and 2 subanalyses were compiled and quality and abovementioned outcomes were compared among studies. Results: A constant decrease in pulmonary vascular resistance and pulmonary arterial pressure was globally reported among the different studies, resulting in increased 6-min walking distance and functional status compared to placebo. Conclusions: Although this evidence clearly shows the benefit of ERAs, studies, which compare ERAs against one another and with other therapies for progressive PAH, have been lacking. Larger and longer studies are necessary to define the role of ERAs as standalone agents and in combination therapies. [ABSTRACT FROM AUTHOR]

Background: Podocytes are major components of the filtration barrier and a renal source of vascular endothelial growth factor (VEGF). Chronic renovascular disease (RVD) progressively degrades the renal function, accompanied by podocyte damage and a progressive reduction in VEGF. We showed that the endothelin (ET) pathway contributes to this pathological process and ET-A (but not ET-B) receptor antagonism protects the kidney in RVD. We hypothesize that ET-A-induced renoprotection is largely driven by the protection of podocyte integrity and function.Methods: To mimic the renal environment of chronic RVD, human podocytes were incubated under chronic hypoxia for 96 h and divided in untreated or treated with an ET-A or ET-B receptor antagonist. Cells were quantified after 96 h. Cell homogenates and media were obtained after 1, 24 and 96 h to quantify production of VEGF, anti-VEGF soluble receptor s-Flt1, and the expression of apoptotic mediators. A separate set of similar experiments was performed after addition of a VEGF-neutralizing antibody (VEGF-NA).Results: Hypoxia decreased podocyte number, which was exacerbated by ET-B but improved after ET-A antagonism. Production of VEGF was preserved by ET-A antagonism, whereas s-Flt1 increased in hypoxic cells after ET-B antagonism only, accompanied by a greater expression of pro-apoptotic mediators. On the other hand, treatment with VEGF-NA diminished ET-A-induced protection of podocytes.Conclusion: ET-A antagonism preserves podocyte viability and integrity under chronic hypoxia, whereas ET-B antagonism exacerbates podocyte dysfunction and death. Enhanced bioavailability of VEGF after ET-A antagonism could be a pivotal mechanism of podocyte protection that significantly contributes to ET-A receptor blockade-induced renal recovery in chronic RVD. [ABSTRACT FROM AUTHOR]

Endothelial cells play a key role in the regulation of vascular tone by the production of mediators such as prostacyclins, nitric oxide and endothelins (ETs). These mediators have opposing roles on the whole vascular bed, including smooth muscle cells, matrix and fibroblasts, as well as platelets and inflammatory pathways. The endothelins are a family of peptides secreted by various cells and tissues in the human. This family consists of 3 isopeptides: ET-1, 2, and 3 in humans which mediate their actions via two ET receptor subtypes: ETA and ETB. These ETs play an important role in human physiology and in the pathophysiology of vasospastic conditions, renal failure, chronic heart failure, atherosclerotic conditions, essential and pulmonary hypertension, pain, malignancy, etc. Accordingly, ET receptor antagonists have been developed rapidly, mostly for the treatment of cardiovascular diseases. But as research progressed, these ET antagonists proved to be disappointing in many clinical trials. This article will focus on the developments in the endothelin field, with special emphasis on the ET-1 antagonists, their clinical use and the shift of research target from ET receptors to endothelin converting enzyme (ECE). Selective inhibitors of ECE along with dual & even triple enzyme inhibitors have come into research. [ABSTRACT FROM AUTHOR]

Aneurysmal subarachnoid hemorrhage (SAH) induces a potent inflammatory cascade that contributes to endothelial dysfunction, imbalance of vasoactive substances (excess endothelin, depletion of nitric oxide), and arterial vasospasm. This process results in delayed cerebral ischemia, a major cause of neurologic disability in those surviving the initial hemorrhage. The only therapy shown to be effective in improving neurologic outcomes after SAH is a calcium-channel antagonist, nimodipine (although it achieved this result without reducing vasospasm). A number of novel therapies have been explored to inhibit the development of vasospasm and reduce the burden of ischemia and cerebral infarction. Statins are promising candidates, as they block multiple aspects of the inflammatory pathway that contributes to ischemic brain injury. Early clinical trials have produced conflicting results, however, and the adoption of statins in clinical practice should await the results of larger, more definitive studies. Though endothelin-receptor antagonists showed promise in significantly reducing vasospasm in preliminary trials, their failure to improve clinical outcomes in phase 3 studies has been disappointing, highlighting the complex link between vasospasm and ischemia. Future directions in the quest to improve outcomes of patients with SAH may need to approach ischemia as a multifactorial process with inflammatory, vasoactive, and ionic/metabolic components. [ABSTRACT FROM AUTHOR]

Abstract: Endothelin-1 (ET-1), a physiological as well as an inflammatory mediator, causes contraction of airway smooth muscles by binding to endothelin-A (ETA) and endothelin-B (ETB) receptors. We investigated the interaction between endothelin receptors on contractions and oxidative stress of bronchial rings of clinically healthy horses. Rings for response studies were set in tissue chambers containing oxygenated Tyrode’s solution. Concentration-response relationships were determined for ET-1 on control rings, rings incubated with ETA antagonist (BQ123), rings incubated with ETB antagonists (IRL 1038 and BQ788), and rings incubated with all antagonists combined. For oxidative stress studies, rings were incubated for 30 minutes separately with ET-1, ETA antagonist + ET-1, ETB antagonists + ET-1, and all three antagonists + ET-1. The control rings were not treated with any agents. Electron paramagnetic resonance (EPR) method was used to measure total reactive oxygen species (ROS), superoxide, and peroxynitrite. Results showed that ET-1 caused dose-dependent contractions which were increased by ETA blockade and decreased by ETB blockade. Combined blockade significantly inhibited the response to ET-1. Regarding the oxidative stress, ET-1 and its antagonists significantly reduced the total ROS. Superoxide production was significantly decreased by ETA antagonist and completely abolished when ETA and ETB antagonists were combined. Peroxynitrite production was not changed significantly. The study suggested that an interaction between ET receptors exists in the expression of contractile responses and oxidative stress. ET-1 attenuated oxidative stress by decreasing total ROS. ETA receptors may be primarily responsible for superoxide production. It appears that ET-1 does not affect peroxynitrite production in normal equine tissues. [Copyright &y& Elsevier]

Pulmonary hypertension in heart failure is associated with exercise intolerance and adverse outcomes. With the availability of multiple drugs that cause pulmonary vasodilation and decrease pulmonary arterial pressure, pulmonary hypertension becomes an attractive therapeutic target. Out of several classes of medications, oral phosphodiesterase inhibitors emerge as the most promising in terms of symptomatic improvement, hemodynamic benefits, reverse cardiac remodeling, and functional capacity. Future trials will show whether the use of these drugs translates to decreased morbidity and mortality in heart failure. [ABSTRACT FROM AUTHOR]

Abstract: Despite multiple advances in prostate cancer therapy, treatment options for castration resistant disease are very limited. While data from recent studies are encouraging, there is no drug that has significantly improved results of standard chemotherapy. Some of the most consistent results are provided by antiangiogenic agents, showing high response rates and manageable toxicity. We describe some of the main therapeutic angiogenesis inhibitors in metastatic castration resistant prostate cancer. These agents include vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, antiangiogenic and inmunomodulatory agents and endothelin receptor antagonists. [Copyright &y& Elsevier]

The evaluation of patients with resistant hypertension should be directed toward confirming true treatment resistance, identifying the causes contributing to treatment resistance (including secondary causes of hypertension), and documenting target-organ damage. Treatment of resistant hypertension is aimed at reversing lifestyle factors contributing to treatment resistance, accurately diagnosing and appropriately treating secondary causes of hypertension, and effectively using multidrug regimens. Lifestyle changes, pharmacologic therapies, and nonpharmacologic therapies have all shown benefits in patients with resistant hypertension, but much additional knowledge is needed to better identify and treat these patients. [ABSTRACT FROM AUTHOR]

It is now becoming clear that two major systems namely the sympathetic nervous system and the renin-angiotensin system are activated in response to ischemic injury; these result in the elevation of plasma catecholamines and angiotensin II during the development of myocardial infarction as well as congestive heart failure. Although plasma levels of several other hormones including aldosterone, endothelin, vasopressin, natriuretic peptides, growth factors and inflammatory cytokines are also increased in heart failure, their relationship with changes in catecholamine and/or angiotensin levels as well as their significance for the induction of congestive heart failure are poorly understood. In this article we have examined the evidence regarding the role of endothelin and vasopressin in the pathogenesis of cardiac hypertrophy and congestive heart failure in addition to evaluating the significance of their antagonism by using their receptor blockade for treatment of congestive heart failure. Endothelin appears to maintain blood pressure by its vasoconstricting action whereas vasopressin primarily produces similar effect by retention of body fluid. Myocardium is also known to express both ET-A and ET-B receptors in addition to V1 and V2 receptors for vasopressin, which have been shown to induce cardiac remodeling. Out of various ET-1 receptor antagonists, which are available, a non-selective endothelin receptor antagonist, bosentan, as well as an ET-A receptor antagonist, BQ-123, seem most promising for the treatment of congestive heart failure. Likewise, vasopressin antagonists such as a non-selective antagonist, conivaptan, as well as V2 selective antagonist, tolvaptan, may prove highly valuable for the therapy of this condition. Since most of the existing interventions are helpful in treating patients with congestive heart failure only partially, there appears to be a real challenge for developing some combination therapy for the treatment of congestive heart failure. [ABSTRACT FROM AUTHOR]

Summary: Background: Endothelin (ET)-1 has been shown to play a significant pathogenic role in pulmonary arterial hypertension (PAH). However, the pathobiological significance of increased ET-1 concentration after administration of ET receptor antagonist in patients with PAH has not yet been fully examined. Methods: In 16 PAH patients, plasma ET-1 concentration was measured at 0, 1, 3, 6, and 24h after a single 62.5mg dose of bosentan, a dual ET receptor antagonist, and the peak and 24-h change in ET-1 concentration from baseline were examined. The severity of PAH was evaluated by hemodynamic parameters, 6-min walk distance, New York Heart Association (NYHA) functional class, and brain natriuretic peptide (BNP). Results: Plasma ET-1 concentration significantly increased from 1.93±0.12 to 3.36±0.18pg/ml after bosentan administration in PAH patients (p <0.01). The peak-to-baseline ratio of ET-1 concentration after bosentan administration showed a significant positive correlation with baseline ET-1 concentration (p <0.05). After 4-week bosentan administration, NYHA functional class improved in 7 patients but was not changed in 9 patients. The optimal cut-off point of % change of ET-1 concentration at 24h for discriminating the two groups was 30%. According to this cut-off point, patients were divided into the higher (n =7) and the lower (n =9) groups. NYHA functional class did not change in the lower group, but significantly improved (p <0.01) in the higher group after 4-week bosentan administration. In addition, plasma BNP levels significantly decreased from baseline in the higher group compared with those in the lower group after 12-week bosentan administration (−44±11% vs. 7±20%, p <0.05). Conclusions: Although the population in this study is small and heterogeneous, measurement of plasma ET-1 concentration after bosentan administration might predict the responsiveness to bosentan treatment, and be useful in the determination of effective therapy in treatment of PAH patients. [Copyright &y& Elsevier]

The article presents a study on the health benefits of sitaxsentan on the treatment of pulmonary arterial hypertension. It aimed to provide 1-year observational data with the two endothelin antagonists sitaxsentan and bosentan. There were patients treated with sitaxsentan at 100 mg. who had 96% overall survival and a 34% risk for a clinical worsening event for 1 year.

Endothelins are a family of peptide compounds which exert regulatory control over cellular processes important for growth, survival, invasion, and angiogenesis. In particular, endothelin-1, acting primarily through the endothelin-A receptor, is implicated in the neoplastic growth of multiple tumor types. In preclinical models, endothelin antagonism inhibits tumor cell proliferation, invasiveness, and new vessel formation, as well as attenuates osteoblastic and pain-related responses to tumor. Clinical testing of an orally bioavailable endothelin antagonist has demonstrated benefit in PSA progression, markers of bone turnover, and pain in men with prostate cancer, but has not demonstrated significant improvement in survival or time to cancer progression. Although this class of drugs is promising for targeted anti-cancer therapy, their role in treatment remains to be defined by completion of future clinical trials. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) appears to be an inappropriate response to an antigen that leads to chronic inflammation rather than repair. This review looks at the role of endothelin-1 (ET-1) as a proinflammatory agent in IBD. ET-1 antagonists in animal models reduce the incidence and severity of IBD. These antagonists may be useful for treatment of IBD in humans. [ABSTRACT FROM AUTHOR]

Abstract: Background: Bosentan, a dual-endothelin receptor antagonist, is an established treatment for pulmonary arterial hypertension. We hypothesized that bosentan is safe and well tolerated in patients with Eisenmenger physiology. Methods: In this pilot open-label study, we primarily examined safety and tolerability of oral bosentan. Patients were recruited from our adult congenital heart clinic following informed consent. Baseline and 3-month assessment included WHO functional class, resting oxygen saturations, 6-min walk test, transthoracic echocardiography and respiratory mass spectrometry. Patient clinical status and liver enzymes were closely monitored throughout. Results: All 10 study patients (42±4 years; eight female) tolerated bosentan well. No major adverse events or significant liver enzyme elevations were observed. All but one patient felt better; none felt worse. Four patients experienced transient leg oedema. Resting oxygen saturations (83±5 versus 80±5%; P=0.011) and the distance travelled in the 6-min walk test (348±112 versus 249±117 m; P=0.004) increased relative to baseline. Changes in echocardiographic parameters (maximum aortic forward flow velocity 1.3±0.1 versus 1.1±0.2 ms, P=0.013; pulmonary arterial acceleration time 66±10 versus 58±12 m/s, P=0.02) and pulmonary blood flow (3.45±1.2 versus 2.58±1.0 L/min, P=0.008) suggested improved pulmonary haemodynamics by study end. Other echocardiographic changes suggested improved right ventricular systolic function (septal amplitude 1.0 versus 1.1 cm, P=0.048; systolic tissue Doppler velocity 4.8 versus 2.3 cm s−1, P=0.002) by study end. Conclusions: Bosentan was safe and well tolerated in adults with Eisenmenger physiology both at initiation and after 3 months of oral therapy. Clinical status of patients and pulmonary haemodynamics appeared to improve, and this warrants further investigation. [Copyright &y& Elsevier]

ABSTRACT Endothelins are powerful vasoconstrictor agents produced by endothelial cells and identified by Yanagisawa et al. in 1988. Two types of receptors for endothelins have been identified: ETA receptors are located on smooth muscle cells of the vascular wall and are responsible for endothelin-induced vasoconstriction while ET B receptors are located on endothelial cells and induce these cells to release NO and prostacyclin. Moreover, these peptides not only cause a potent and prolonged vasoconstriction but are also known to enhance cell proliferation and to stimulate extracellular matrix accumulation. High levels of plasma or tissue endothelins have been found in patients with heart failure, diabetes, stroke, primary pulmonary hypertension, liver cirrhosis and other diseases. Given these effects of endothelins, blocking their receptors might be a new way to reduce blood pressure and to treat other illnesses. Accordingly, many endothelin antagonists have been developed and evaluated in animals and humans. Enrasentan is a mixed ETA and ETB receptor antagonist with a higher affinity for ETA receptors, although it cannot be considered a selective antagonist. In an animal model of hypertension and cardiac hypertrophy the drug has reduced blood pressure, prevented cardiac hypertrophy and preserved myocardial function. In rats with hyperinsulinemia and hypertension enrasentan normalized blood pressure and prevented cardiac and renal damage. In rats with stroke the drug reduced the ischemic area in the brain. Enrasentan has been added to conventional treatment in patients with heart failure (NYHA Class 2-3) and no addictive effect of the drug has been observed. This is in contrast with results obtained in animal models and still has not been explained. In conclusion, many possible clinical applications can be suggested for this drug, but further studies are necessary to better evaluate its therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Background. It is recognized that endothelins are released in response to hypoperfusion and anoxia of the kidney and may be responsible for the consequent deterioration in renal function. This study examined the ability of a non‐selective (SB209670) and ETA‐selective (UK‐350,926) endothelin antagonist to attenuate ischaemia‐induced renal failure in unilaterally nephrectomized rats. [ABSTRACT FROM PUBLISHER]

Endothelins are a family of peptides, which comprises endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), each containing 21 amino-acids. ET-1 is a peptide secreted mostly by vascular endothelial cells, the predominant isoform expressed in vasculature and the most potent vasoconstrictor currently known. ET-1 also has inotropic, chemotactic and mitogenic properties. In addition, it influences salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide and stimulates the sympathetic nervous system.The overall action of endothelin is to increase blood pressure and vascular tone. Therefore, endothelin antagonists may play an important role in the treatment of cardiac, vascular and renal diseases associated with regional or systemic vasoconstriction and cell proliferation, such as essential hypertension, pulmonary hypertension, chronic heart failure and chronic renal failure. Long-term anti-endothelin therapy may improve symptoms and favourably alter the progression of heart failure.Endothelin appears to participate in induction and progression of sclerotic renal changes, leading to progression to end-stage renal disease. Anti-endothelin therapy might offer additional benefits in the prevention of progression of chronic renal failure in addition to the known benefits of RAAS inhibition.Clinical trials have demonstrated potentially important benefits of endothelin antagonists for patients with essential hypertension, pulmonary hypertension and heart failure. Further studies are necessary to determine the role of anti-endothelin therapy in the treatment of cardiovascular diseases and determine the different roles of selective receptor antagonism vs. mixed ETA/B-receptor antagonism in human diseases. [ABSTRACT FROM PUBLISHER]

Heart failure is characterized both by an activation of the endothelin system and an increased vasoconstrictor contractile response to the peptide. Given its pharmacological profile, it is likely that endothelin (ET-1) plays a deleterious role in the development of heart failure, and that blockers of the endothelin system are beneficial in this disease. Indeed, in rats with heart failure, ETA and dual ETA-ETB receptor antagonists reduce arterial pressure as well as left ventricular end diastolic pressure. The same antagonists also prevent the degradation of left ventricular function, as evidenced by the increased left ventricular fractional shortening and wall thickening. ETA and ETA-ETB antagonists also reduce LV dilatation and LV fibrosis, but do not affect LV hypertrophy. Moreover, comparison between selective ETA and combined ETA-ETB antagonists reveal no differences in terms of their effects on blood pressure, LV hemodynamics or remodeling. However, only combined ETA-ETB antagonists significantly decreased heart rate. ETB antagonists alone do not affect blood pressure or LV hemodynamics, but reduce LV fibrosis. With regard to survival, we have shown that long term treatment with the dual ETA-ETB antagonist bosentan increased survival to the same extent as an angiotensin converting enzyme inhibitor. However, the effect of selective ETA antagonists on survival is more controversial, since we found that the non-peptide ETA antagonists LU 135252 did not affect survival of rats with myocardial infarction, while others have shown that the peptide ETA antagonist BQ-123 increased survival in the same model. These conflicting data regarding the efficacy of selective ETA vs dual ETA-ETB blockade points out the need for controlled long term studies comparing the effects of theses two pharmacological approaches on survival. [ABSTRACT FROM AUTHOR]

Endothelin-1, a member of a novel family of regulatory peptides, is the most potent vasoconstrictor and pressor substance known. Endothelin-1 is a 21-amino-acid endothelium-derived peptide causing uniquely sustained vasoconstriction. In addition, endothelin-1 has pronounced effects on the coronary, renal and cerebral circulations, enhances responses to other vasoconstrictors, and is comitogenic. Recent studies have shown that the endothelins are essential for normal fetal development, and that endothelin-1 plays an important physiological role in the regulation of basal vascular tone and blood pressure in healthy humans.There is now also a wealth of evidence suggesting that endothelin-1 is a key mediator in a range of cardiovascular diseases associated with sustained vasoconstriction, such as chronic heart failure, and with vasospasm, such as subarachnoid haemorrhage. In addition, endothelin-1 appears to act in opposition to nitric oxide to promote the atherosclerotic process. There are a large number of oral and intravenously active endothelin antagonists entering clinical development and a number of clinical studies, particularly with endothelin receptor antagonists, are now under way. Such studies are beginning to define the role of the endothelins in cardiovascular disease and to confirm the potential of the endothelin system as an important new therapeutic target. [ABSTRACT FROM PUBLISHER]

The rapid development of endothelin-receptor antagonists has made the endothelin pathway a new therapeutic target in the treatment of cardiovascular diseases, only ten years after the report of its discovery. While the first clinical trials will help to position this new family of compounds in our therapeutic armament for the treatment of essential or secondary forms of hypertension, several preclinical chronic studies already provide a picture of what we can expect from these drugs. Endothelin-receptor antagonists are not effective in all experimental models of hypertension, but those that respond present hypertrophy of small arteries, secondary to a local overexpression of the peptide. Although angiotensin II seems to represent a stimulus for endothelin overexpression in some models, other, as yet undetermined, stimuli are likely in others. Besides their narrow spectrum of antihypertensive activity, endothelin-receptor antagonists may also protect from complications of hypertension by improving end-organ function in a pressure-independent manner. This seems to be the case for the structure and reactivity of resistance arteries, as well as for renal damage. However, it is not clear at this point if cardiac structure and function are improved beyond the benefits produced by blood pressure reduction. The first results in essential hypertensive subjects suggest some degree of efficacy of endothelin-receptor antagonists. Other clinical trials will help to determine if secondary forms of the disease benefit equally or more from this new class of drugs, and if end-organ damage can be reduced beyond blood-pressure reduction. [ABSTRACT FROM PUBLISHER]

Background: Endothelins (ET) are a family of peptides that act as potent vasoconstrictors and pro-fibrotic growth factors. ET-1 is integral to renal and cardiovascular pathophysiology and exerts effects via autocrine, paracrine and endocrine signaling pathways tied to regulation of aldosterone, catecholamines, and angiotensin. In the kidney, ET-1 is critical to maintaining renal perfusion and controls glomerular arteriole tone and hemodynamics. It is hypothesized that ET-1 influences the progression of chronic kidney disease (CKD), and the objective of this review is to discuss the pathophysiology, and role of ET and endothelin receptor antagonists (ERAs) in CKD., Summary: The use of ERAs in hypertensive nephropathy has the potential to decrease proteinuria, and in diabetic nephropathy has the potential to restore glycocalyx thickness, also decreasing proteinuria. Focal segmental glomerular sclerosis has no specific Food and Drug Administration-approved therapy currently, however, ERAs show promise in decreasing proteinuria and slowing tissue damage. ET-1 is a potential biomarker for autosomal dominant polycystic kidney disease progression and so it is thought that ERAs may be of some therapeutic benefit., Key Messages: Multiple studies have shown the utility of ERAs in CKD. These agents have shown to reduce blood pressure, proteinuria, and arterial stiffness. However, more clinical trials are needed, and the results of active or recently concluded studies are eagerly awaited., Competing Interests: The authors have no conflicts of interest to disclose and the results in this paper have not been published previously in whole or part., (Copyright © 2019 by S. Karger AG, Basel.)