Effect of endothelin antagonists on the responses to prostanoid endothelium-derived contracting factor.

1. The effect of endothelin antagonists on endothelium-dependent contractions was studied in conditions of stimulated endothelium-derived contracting factor (EDCF) release and with exogenous activation of thromboxane A2-endoperoxide receptors in the rat aorta. 2. The incubation of aortic rings with N omega-nitro-L-arginine methyl ester (L-NAME) led to EDCF-mediated contraction upon stimulation with acetylcholine (24 +/- 3% of KCl contraction). When vessels were preincubated with bosentan, an endothelinA- and endothelinB-receptor antagonist, in addition to L-NAME, acetylcholine-induced contraction was reduced to 8 +/- 2% (P < 0.01) of KCl contractions. PD147953, a selective endothelinA-receptor antagonist, reduced the contraction to 14 +/- 4% (P < 0.05) of KCl contractions. 3. Bosentan preincubation produced a significant parallel rightward shift of the contractions to U46619, a selective thromboxane A2 receptor agonist. In contrast, PD147953 failed to exhibit any inhibitory effect on U46619 contractions. 4. These results suggest that endothelin antagonists inhibit EDCF-mediated contractions by blocking endothelinA receptors and that, in addition, bosentan antagonizes the direct stimulation of thromboxane A2 receptors.