Endothelial cell-specific ETB receptor knockout: Autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1

N. F. Kelland, R. E. Kuc, D. L. McLean, A. Azfer, A. J. Bagnall, G. A. Gray, F. H. Gulliver-Sloan, J. J. Maguire, A. P. Davenport, Y. V. Kotelevtsev, D. J. Webb

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55 Citations (Scopus)

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 [125I]ET-1 was impaired in EC ETB-/-mice. Pretreatment with the selective ETB antagonist A192621 impaired [125I]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.

Original languageEnglish
Pages (from-to)644-651
Number of pages8
JournalCanadian Journal of Physiology and Pharmacology
Volume88
Issue number6
DOIs
Publication statusPublished - Jun 2010
Externally publishedYes

Keywords

  • Autoradiography
  • Clearance
  • Endothelin
  • Endothelium
  • Genetic knockout models
  • Mice

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