Endothelins release tissue plasminogen activator and prostanoids

Endothelin (ET)-1 (0.1-1 nmol/kg), ET-2 (0.1-1 nmol/kg) or ET-3 (0.3-3 nmol/kg) dose dependently inhibited platelet aggregation induced by adenosine di-phosphate (ADP) ex vivo in anaesthetised rabbits, while having no effect on aggregations induced by ADP, collagen or arachidonic acid in vitro. This anti-aggregatory effect of the peptides is most likely due to the release of prostacyclin into the circulation, for the inhibition was abolished by an injection of indomethacin (5 mg/ml). All three peptides produced a significant, bi-phasic reduction of the euglobulin clot lysis time. This ET-induced enhancement of plasma fibrinolytic activity was associated with a release of tissue plasminogen activator into the circulation. ET-1 or ET-2 caused a transient decrease in left ventricular systolic pressure (LVSP) followed by a prolonged pressor response. However, ET-3, while inducing a similar transient fall in LVSP caused a second, more prolonged, decrease in LVSP. The haemodynamic responses to all three peptides were modulated by the release of prostanoids, as evidenced by the elevation of the pressure responses by indomethacin.