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

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Abstract
Astrocytes are known to possess an effective endothelin (ET) eliminatory system which involves astrocytic ETA and ETB 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 ETB receptors. The results revealed (1) a hypoxia‐mediated decrease of extracellular ET‐1 in wildtype astrocytes (+/+) 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 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 ETB 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 ETB receptors. ETB deficiency, whether genetic or experimentally induced, impairs elimination of extracellular ET‐1. GLIA 34:18–26, 2001.