EFFECT OF ENDOTHELIN ANTAGONISTS ON THE RESPONSES TO PROSTANOID ENDOTHELIUM-DERIVED CONTRACTING FACTOR

1 The effect of endothelin antagonists on endothelium-dependent contra ctions was studied in conditions of stimulated endothelium-derived con tracting factor (EDCF) release and with exogenous activation of thromb oxane A(2)-endoperoxide receptors in the rat aorta. 2 The incubation o f aortic rings with NO-nitro-L-arginine methyl ester (L-NAME) led to E DCF-mediated contraction upon stimulation with acetylcholine (24+/-3% of KCl contraction). When vessels were preincubated with bosentan, an endothelin(A)- and endothelin(B)-receptor antagonist, in addition to L -NAME, acetylcholine-induced contraction was reduced to 8+/-2% (P<0.01 ) of KCl contractions. PD147953, a selective endothelin(A)-receptor an tagonist, reduced the contraction to 14+/-4% (P<0.05) of KCl contracti ons. 3 Bosentan preincubation produced a significant parallel rightwar d shift of the contractions to U46619, a selective thromboxane A(2) re ceptor agonist. In contrast, PD147953 failed to exhibit any inhibitory effect on U46619 contractions. 4 These results suggest that endotheli n antagonists inhibit EDCF-mediated contractions by blocking endotheli n(A) receptors and that, in addition, bosentan antagonizes the direct stimulation of thromboxane A(2) receptors.