OBJECTIVES: We report in the present study the role of endothelin (ET-1) and ET-1 receptors in the sustained hypoxia-induced systemic hypertension. METHODS: Wistar rats were randomly assigned to live continuously in hypobaric hypoxia (CH rats) or normoxia (N rats). At the end of hypoxic stress exposure (5 weeks at 450 mm Hg), measurements of mean systemic arterial pressure were done. The effects of ET-1 in the presence or not of the endothelium and/or of specific ET-A inhibitors (BQ-123) or ET-B inhibitors (BQ-788), have been investigated in an isolated model of rat thoracic aorta. Finally, plasmatic ET-1 concentrations have been determined by assay procedure. RESULTS: Following five weeks of chronic hypoxic stress, CH rats presented a significant increase of mean systemic arterial pressure (N: 129.1+/-6.8 mm Hg vs CH: 152.5+/-3.4 mm Hg; P<0.05). Despite of this hypoxia-induced hypertension, ET-1 plasmatic concentration was not different between N and CH rats. Finally, CH rats presented a reduce response to ET-1 when compared to N rats. This phenomenon seems to be associated to the ET-A vascular smooth muscle cell receptors, since difference between N and CH rats was still present in endothelium denuded aortic rings in the presence or not of the specific ET-B inhibitors (BQ-788). In addition, in the presence of the specific ET-A inhibitor (BQ-123) response to ET-1 was abolished in N and CH rats to the same extent (N:-98%; CH:-99%). CONCLUSION: This work clearly suggests that, following long term exposure to hypoxia, ET-1 and ET-1 receptors are not involved in the persistence of systemic hypertension in a rat model, and that chronic exposure to severe hypoxic stress was associated with a downregulation of the ET-A receptors response to ET-1.