Role of the astrocytic ETB receptor in the regulation of extracellular endothelin-1 during hypoxia

Astrocytes are known to possess an effective endothelin (ET) eliminatory sy stem which involves astrocytic ETA and ETB receptors and may become particu larly relevant under pathophysiological conditions. The present study has t herefore been designed to explore the effect of standardized hypoxia on ext racellular concentrations of endothelin-1 (ET-1) and on endothelin-converti ng enzyme (ECE) activity in primary rat astrocytes genetically (sl/sl) or e xperimentally (dexamethasone) deficient in ETB receptors. The results revea led (1) a hypoxia-mediated decrease of extracellular ET-1 in wildtype astro cytes (+/+) that was not observed in ETB-deficient (sl/sl) cultures; (2) an ET receptor antagonist-induced increase in ET-1 in the media of both genot ypes with further elevation upon hypoxia in +/+ cultures only; (3) augmenta tion of the dexamethasone-induced increase in extracellular ET-1 by hypoxia in +/+, but not in sl/sl cultures; (4) synergistic reduction of ETB gene t ranscription by hypoxia and dexamethasone; and (5) significant increases in endothelin-converting enzyme activity in the presence of hypoxia. To concl ude, hypoxia stimulates astrocytic release of mature ET-1, This stimulation is (over)compensated for by increased ET-1 binding to functional ETB recep tors. ETB deficiency, whether genetic or experimentally induced, impairs el imination of extracellular (C) 2001 Wiley-Liss, Inc.