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Can J Physiol Pharmacol ; 88(6): 644-51, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20628430

ABSTRACT

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB(-/-)) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB(-/-) mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB(-/-) mice and controls, despite increased concentration of plasma ET-1 in EC ETB(-/-). Clearance of an intravenous bolus of [(125)I]ET-1 was impaired in EC ETB(-/-) mice. Pretreatment with the selective ETB antagonist A192621 impaired [(125)I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB(-/-) mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.


Subject(s)
Endothelin-1/pharmacokinetics , Endothelium, Vascular/metabolism , Receptor, Endothelin B/genetics , Animal Structures/metabolism , Animals , Autoradiography , Blood Vessels/metabolism , Endothelial Cells/metabolism , Endothelin B Receptor Antagonists , Endothelin-1/administration & dosage , Endothelin-1/genetics , Gene Expression/genetics , Histocytochemistry , Kidney Glomerulus/metabolism , Kidney Medulla/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Mice, Knockout , Mice, Transgenic , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Proteins/genetics , Pyrrolidines/pharmacology , RNA, Untranslated , Receptor Protein-Tyrosine Kinases/genetics , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Receptor, TIE-2 , beta-Galactosidase/metabolism
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