The presence of functional endothelin ETB receptors was investigated in rat isolated mesenteric resistance arteries. Neither endothelin-3 (0.1-100 nM) nor the endothelin ETB selective agonists sarafotoxin S6c and BQ 3020 (both 1-100 nM) induced any measurable hyperpolarization or relaxation in stimulated (alpha 1-adrenoceptor agonist; phenylephrine) or unstimulated arteries. In both cases, the subsequent addition of acetylcholine (1 microM) hyperpolarized the membrane potential by 10-20 mV and totally reversed any contraction which was present. These results indicate that the endothelin ETB-mediated vasodilatation observed in the intact mesenteric bed does not reflect hyperpolarization of smooth muscle cells in resistance arteries arising from the mesenteric artery.
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http://dx.doi.org/10.1016/s0014-2999(96)00839-4 | DOI Listing |
BJC Rep
January 2025
Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France.
Background: Endothelin 1 receptors are one of the drivers of tumor progression in many cancers. Inhibition of their signaling pathways with antagonist drugs has been the subject of numerous clinical trials, but the results have not met expectations probably due to the high endothelin concentrations in the tumor microenvironment and their unusually high affinity for their receptors.
Methods: We previously reported the rendomab B49 antibody (RB49) exhibiting a preferential affinity for the activated conformation of human endothelin B receptor (ET), not displaced by high endothelin levels, and without any pharmacological properties that could inhibit the division of melanoma cells.
Exp Neurol
March 2025
Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA; Department of Neurological Sciences and Neuroscience Graduate Program, University of Vermont, Burlington, VT 05401, USA. Electronic address:
Reciprocal communication between reactive astrocytes and microglial cells provides local, coordinated control over critical processes such as neuroinflammation, neuroprotection, and scar formation after CNS injury, but is poorly understood. The vasoactive peptide hormone endothelin (ET) is released and/or secreted by endothelial cells, microglial cells and astrocytes early after ischemic stroke and other forms of brain injury. To better understand glial cell communication after stroke, we sought to identify paracrine effectors produced and secreted downstream of astroglial endothelin receptor B (ETB) signaling.
View Article and Find Full Text PDFEur J Pharmacol
February 2025
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 PDFACS Chem Biol
January 2025
Department Chemistry and Biochemistry Clemens-Schöpf-Institute, Technical University Darmstadt, Peter-Grünberg Straße 4, Darmstadt 64287, Germany.
Class A G protein-coupled receptors (GPCRs) are key mediators in numerous signaling pathways and important drug targets for several diseases. A major shortcoming in GPCR ligand screening is the detection limit for weak binding molecules, which is especially critical for poorly druggable GPCRs. Here, we present a proximity-based screening system for class A GPCRs, which adopts the natural two-step activation mechanism of class B GPCRs.
View Article and Find Full Text PDFFront Pharmacol
November 2024
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.
Methods: A mathematical model of ET-1 kinetics was developed to quantify effects of ET antagonist exposure and selectivity on concentrations of ET-1 and its complexes with ET and ET receptors.
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