Endothelins: potent releasers of prostacyclin and EDRF

The isopeptides endothelin-1 (ET-1) and endothelin-3 (ET-3) are potent vasoconstrictor substances in pithed or chemically-denervated rats. However, when injected into anesthetized rats with a high resting blood pressure, these peptides have vasodepressor actions. In addition, the pressor effects were potentiated by indomethacin indicating that release of endogenous eicosanoids modulated the pressor responses. Endothelin-1 released eicosanoids from a number of perfused isolated organ preparations. Prostacyclin and thromboxane A2 were released from perfused guinea-pig lungs, prostaglandin E2, prostacyclin and thromboxane A2 from rabbit spleen and prostacyclin and thromboxane A2 from rabbit kidneys. The eicosanoids were identified both by bioassay and by radioimmunoassay. Injection of ET-1 or ET-3 into the mesenteric artery of the rat isolated perfused mesentery preparation caused dose-related reductions in perfusion pressure. These depressor effects could be abolished by removing the endothelium with deoxycholate or by perfusing with oxyhaemoglobin, indicating that they were caused by release of EDRF. Endothelin-1 also released EDRF, identified by bioassay, from the endothelium of a perfused rabbit aorta. Endothelin-1 and ET-3 injected into anesthetized rabbits inhibited ex vivo platelet aggregation by increasing cyclic AMP, presumably through the release of prostacyclin into the circulation. Thus, endothelins release prostacyclin and EDRF both in vitro and in vivo.