In vitro studies have indicated increased endothelial release of endothelin during tissue and cellular hypoxia. Therefore, we studied the effect of tourniquet ischaemia and venous stasis on plasma endothelin-1 (ET-1) levels in humans in vivo. The effect of hypoxia on plasma ET-1 levels in 16 patients subjected to an orthopaedic operation and six healthy volunteers was studied by (a) tourniquet ischaemia, in which a limb is totally emptied of blood and kept ischaemic by means of a pneumatic tourniquet, and (b) venous stasis in an upper arm. The mean (SEM) basal plasma ET-1 concentration in the patients subjected to tourniquet ischaemia of a lower limb was 4.1 (1.0) pg ml-1. No significant change in plasma ET-1 levels during or after tourniquet ischaemia was found. The mean (SEM) plasma ET-1 concentration in six healthy subjects prior to venous occlusion in the right upper arm was 3.3 (0.7) and 2.7 (0.3) pg ml-1 in the right and left arm, respectively. A significant increase in plasma ET-1 concentration after 20 min was observed in the arm subjected to venous stasis, but not in the other, control, arm. Mean arterial blood pressure did not change significantly. Local tissue hypoxia may not be an important stimulus for ET-1 release in humans in vivo, whereas short-term venous occlusion in an upper arm leads to local release of ET-1 by an as yet unknown mechanism.