title: Downregulation of endothelin receptors by autocrine production of endothelin-1.
abstract: The potent vasoconstrictor endothelin-1 (ET-1) is a paracrine, but also autocrine, factor for some types of cells. The goal of our study was to evaluate whether the receptor population in cells expressing endothelin receptor subtype A (rat mesangial cells) or endothelin receptor subtype B (human and rat endothelial cells) was affected by the autocrine production of ET-1. We therefore studied maximal binding capacity of 125I-labeled ET-1 in the presence or absence of the metalloprotease inhibitors phosphoramidon, which blocks the intracellular processing of Big ET-1 to ET-1, and thiorphan, which does not block this conversion. Phosphoramidon inhibited the release of ET-1 by human umbilical vein endothelial cells, rat aortic endothelial cells, and rat mesangial cells, and increased 1.4- to 17-fold the maximal binding capacity in the three types of cells. Thiorphan affected neither ET-1 release nor binding. The increase in receptor binding by phosphoramidon was associated with an increase in the functional effect of ET-1, as measured by arachidonic acid release in rat mesangial cells. We conclude that autocrine production of ET-1 decreases, either by binding or by downregulation, the number of binding sites available for ET-1 of paracrine or systemic sources. This aspect of modulation of the vasoconstrictor effect of endothelin should be considered in pathological situations or after endothelin-converting-enzyme inhibition.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Clozel
authors.forename: B M
authors.initials: BM
authors.lastname: Löffler
authors.forename: V
authors.initials: V
authors.lastname: Breu
authors.forename: L
authors.initials: L
authors.lastname: Hilfiger
authors.forename: J P
authors.initials: JP
authors.lastname: Maire
authors.forename: B
authors.initials: B
authors.lastname: Butscha
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media; D015536:Down-Regulation; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D009994:Osmolar Concentration; D017466:Receptors, Endothelin / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology / Q000378:metabolism
chemical_list: D003470:Culture Media; D016232:Endothelins; D006020:Glycopeptides; D017466:Receptors, Endothelin; D016718:Arachidonic Acid; C008890:phosphoramidon