ET_B receptor antagonist, IRL 1038, selectively inhibits the endothelin-induced endothelium-dependent vascular relaxation

In isolated rat aorta, endothelin-1 induced contractions at lower concentrations than endothelin-3. The contractile effects were augmented by removing the endothelium. In contrast, endothelin-1 and endothelin-3 at similar concentrations induced endothelium-dependent relaxation in norepinephrine-stimulated aorta. IRL 1038 ([Cys¹¹, Cys¹⁵]endothelin-1(11-21); 3 μM) augmented the contractile effects of endothelins only in the presence of the endothelium. IRL 1038 (0.3-3 μM) inhibited the endothelium-dependent relaxation induced by endothelins but not by carbachol. IRL 1038 itself did not change muscle tension. These results suggest that IRL 1038 is a novel antagonist of the ET_B receptor responsible for the release of relaxing factor from the vascular endothelium.