Role of the astrocytic ET(B) receptor in the regulation of extracellular endothelin-1 during hypoxia.
Astrocytes are known to possess an effective endothelin (ET) eliminatory system which involves astrocytic ET(A) and ET(B) receptors and may become particularly relevant under pathophysiological conditions. The present study has therefore been designed to explore the effect of standardized hypoxia on extracellular concentrations of endothelin-1 (ET-1) and on endothelin-converting enzyme (ECE) activity in primary rat astrocytes genetically (sl/sl) or experimentally (dexamethasone) deficient in ET(B) receptors. The results revealed (1) a hypoxia-mediated decrease of extracellular ET-1 in wildtype astrocytes (+/+) that was not observed in ET(B)-deficient (sl/sl) cultures; (2) an ET receptor antagonist-induced increase in ET-1 in the media of both genotypes with further elevation upon hypoxia in +/+ cultures only; (3) augmentation of the dexamethasone-induced increase in extracellular ET-1 by hypoxia in +/+, but not in sl/sl cultures; (4) synergistic reduction of ET(B) gene transcription by hypoxia and dexamethasone; and (5) significant increases in endothelin-converting enzyme activity in the presence of hypoxia. To conclude, hypoxia stimulates astrocytic release of mature ET-1. This stimulation is (over)compensated for by increased ET-1 binding to functional ET(B) receptors. ET(B) deficiency, whether genetic or experimentally induced, impairs elimination of extracellular ET-1.
Department of Neurology, Georg-August-University, Göttingen, Germany.
M
M
Hasselblatt
P
P
Lewczuk
B M
BM
Löffler
H
H
Kamrowski-Kruck
N
N
von Ahsen
A L
AL
Sirén
H
H
Ehrenreich
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000187:drug effects / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D004921:Erythropoietin / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008666:Metalloendopeptidases; D010666:Phenylpropionates / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000172:deficiency / Q000378:metabolism*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C113044:LU 224332; D010666:Phenylpropionates; D011422:Propionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D004921:Erythropoietin; C107831:darusentan; D003907:Dexamethasone; D007770:L-Lactate Dehydrogenase; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D005947:Glucose