title: Phorbol ester promotes a sustained down-regulation of endothelin receptors and cellular responses to endothelin in human vascular smooth muscle cells.
abstract: The effect of phorbol ester pretreatment of human vascular smooth muscle cells (hVSMC) was studied with respect to regulation of endothelin (ET)-receptor binding and cellular responses to ET. The capacity of hVSMC to bind ET was decreased (by approximately 50% at maximum) after phorbol exposure, and this reductive effect was both rapid (t 1/2 approximately 10 min.) and sustained (for up to 24 hrs. of chronic phorbol exposure). Phorbol pretreatment inhibited both inositol phosphate and diacylclycerol production responses of hVSMC to ET in a manner that was time-dependent and sustained. Phorbol pretreatment also produced a persistent reduction in the ability of ET to release isotopically-labelled arachidonic and/or its metabolites from hVSMC, but importantly ionomycin-stimulated release was similarly negatively affected. Furthermore, ET-induced accumulation of the phospholipase A2/phospholipase B-derived inositol phospholipid metabolite, glycerophosphoinositol, was not different between control and phorbol-treated hVMSC. The mechanism whereby phorbol exerts differential, but notably sustained inhibitory effects on ET-promoted signal transduction pathways are thus complex and illustrative of the selectivity of protein kinase C in regulating cellular responses.
authors.affiliation: Department of Research, University Hospital, Basel, Switzerland.
authors.forename: T J
authors.initials: TJ
authors.lastname: Resink
authors.forename: T
authors.initials: T
authors.lastname: Scott-Burden
authors.forename: E
authors.initials: E
authors.lastname: Weber
authors.forename: F R
authors.initials: FR
authors.lastname: Bühler
mesh_terms: D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002478:Cells, Cultured; D004075:Diglycerides / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D016232:Endothelins; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D007294:Inositol / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009852:Omentum; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D017466:Receptors, Endothelin; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D001095:Arachidonic Acids; D004075:Diglycerides; D016232:Endothelins; D007295:Inositol Phosphates; D010455:Peptides; D011956:Receptors, Cell Surface; D017466:Receptors, Endothelin; D016718:Arachidonic Acid; D007294:Inositol; D013755:Tetradecanoylphorbol Acetate