Since the discovery of the endothelin system in 1988, it has been implicated in numerous physiological and pathological phenomena. In the cardiovascular system, endothelin-1 (ET-1) acts through intracellular pathways of two endothelin receptors (ETA and ETB) located mainly on smooth muscle and endothelial cells to regulate vascular tone and provoke mitogenic and proinflammatory reactions. The endothelin ETA receptor is believed to play a pivotal role in the pathogenesis of several cardiovascular disease including systemic hypertension, pulmonary arterial hypertension (PAH), dilated cardiomyopathy, and diabetic microvascular dysfunction. Growing evidence from recent experimental and clinical studies indicates that the blockade of endothelin receptors, particularly the ETA subtype, grasps promise in the treatment of major cardiovascular pathologies. The simultaneous blockade of endothelin ETB receptors might not be advantageous, leading possibly to vasoconstriction and salt and water retentions. This review summarizes the role of ET-1 in cardiovascular modulation and the therapeutic potential of endothelin receptor antagonism.
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Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy.
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Department of Cardiovascular Sciences, University of Leicester, Leicester, Leicestershire, UK.
Introduction: Endothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation, and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss.
View Article and Find Full Text PDFALIGNing the treatment of IgA nephropathy: Reducing proteinuria with endothelin A receptor inhibition.
Med
January 2025
Cambridge University Hospital NHS Trust, Hills Road, Cambridge CB2 2QQ, UK. Electronic address:
The ALIGN trial demonstrates that atrasentan, an endothelin A (ETA) receptor antagonist, reduces proteinuria in patients with IgA nephropathy (IgAN), a key goal to slow progressive renal disease. These results are consistent with those from sparsentan, a combined ETA and angiotensin inhibitor, in IgAN, suggesting two-year data will show atrasentan improves renal outcomes.
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Department of Physiology, School of Medicine, University of Valencia, Spain; Institute of Health Research INCLIVA, Valencia, Spain; Center for Biomedical Research Network on Cardiovascular Diseases (CIBER-CV), Madrid, Spain. Electronic address:
Sympathetic nervous system (SNS), endothelin 1 (ET-1) and angiotensin II (Ang II) are involved in the pathophysiology of acute myocardial infarction (AMI). Valproic acid (VPA) is under study for the treatment against AMI due to its beneficial cardiac effects. However, the vascular effects of VPA on the activation of the SNS, ET-1 and Ang II after AMI are not fully studied.
View Article and Find Full Text PDFKinetics of endothelin-1 and effect selective ET antagonism on ET activation: a mathematical modeling analysis.
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Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gaithersburg, MD, United States.
Introduction: Endothelin-1 (ET-1) regulates renal and vascular function, but the clinical utility of selective ET receptor antagonists has been limited due to associated fluid retention. The mechanisms underlying fluid retention remain poorly understood but could be a consequence of changes in ET-1 binding to the unantagonized ET receptor, either through increased ET-1 or non-selective ET.
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Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ET) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials.
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