title: ETA and ETB receptor antagonists synergistically increase extracellular endothelin-1 levels in primary rat astrocyte cultures.
abstract: Astrocytes produce and bind endothelins (ETs), suggesting that these cells have ET autoregulatory and eliminatory functions. To further investigate these functions in primary rat astrocytes, ET-1 levels in the cell culture media (RIA/HPLC) and intracellular content of ET-1 mRNA (RT PCR) were measured under basal and stimulated (thrombin, 2.2 U/ml) conditions in the presence and absence of ETA and ETB selective antagonists (BQ123 or LU135252, and BQ788, respectively). Neither basal nor stimulated ET-1 levels in astrocyte media were influenced by ETA or ETB antagonists alone, but were significantly increased by a combination of both. ir ET-3 levels were not affected by antagonist treatment. Exogenous ET-1, added to the cultures, was rapidly cleared from the supernatant; this clearance was markedly inhibited by a combination of BQ123 and BQ788. ET-1 mRNA levels were not altered by any treatment. To conclude, in primary rat astrocyte cultures, extracellular ET-1 is cleared by binding to ET-receptors, apparently involving both, ETA and ETB sites. Thus, a blockade of the astrocytic ET eliminatory function as a consequence of the in vivo application of non-selective ET receptor antagonists may lead to increased extracellular ET levels in the brain.
authors.affiliation: Department of Neurology, Georg-August-University, and Max-Planck-Institute for Experimental Medicine, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hasselblatt
authors.forename: H
authors.initials: H
authors.lastname: Kamrowski-Kruck
authors.forename: N
authors.initials: N
authors.lastname: Jensen
authors.forename: L
authors.initials: L
authors.lastname: Schilling
authors.forename: H
authors.initials: H
authors.lastname: Kratzin
authors.forename: A L
authors.initials: AL
authors.lastname: Sirén
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001667:Binding, Competitive; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000378:metabolism; D019334:Endothelin-3 / Q000096:biosynthesis; D006629:Hirudins / Q000494:pharmacology; D007700:Kinetics; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013917:Thrombin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D019334:Endothelin-3; D006629:Hirudins; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010666:Phenylpropionates; D010880:Piperidines; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; C107831:darusentan; C086539:BQ 788; D013917:Thrombin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)