Novel antagonist of endothelin ET_B1 and ET_B2 receptors, BQ-788: Effects on blood vessel and small intestine

The effects of a peptide, BQ-788 [N-cis-2,6-dimethyl-piperidinocarbonyl-L-γ-methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine], on isolated blood vessel and small intestine were examined. In the rat aorta, BQ-788 antagonized the endothelium-dependent, ET_B1 receptor-mediated relaxation due to endothelin (ET)-3 with EC₅₀ of 3 μM. In the rat aorta without endothelium, 10 μM BQ-788 weakly antagonized the ET_A1-mediated contractile effects of ET-1 and ET-3. In the rabbit saphenous vein, it has been shown that ET_A1, ET_A2, ET_B1 and ET_B2 receptors mediate contraction. BQ-788 (10 μM) almost completely inhibited the contractile effect of sarafotoxin S6c (an ET_B1 and ET_B2 agonist). BQ-788 also antagonized the contractile effect of ET-3 (an ET_A1, ET_B1 and ET_B2 agonist) more strongly than desensitization of ET_B1 and ET_B2 receptors. However, BQ-788 did not antagonize the effect of ET-1 (agonist of all four receptors). In the guinea pig ileum, 10 μM BQ-788 completely inhibited the relaxation mediated by ET_B1 and ET_B2 receptors. These results suggest that BQ-788 is a novel antagonist of ET_B1 and ET_B2 receptors with weak antagonistic effect on the ET_A1 receptor.