Novel antagonist of endothelin ETB1 and ETB2 receptors, BQ-788: effects on blood vessel and small intestine.

The effects of a peptide, BQ-788 [N-cis-2, 6-dimethyl-piperidinocarbonyl-L-gamma-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, ETB1 receptor-mediated relaxation due to endothelin (ET)-3 with EC50 of 3 microM. In the rat aorta without endothelium, 10 microM BQ-788 weakly antagonized the ETA1-mediated contractile effects of ET-1 and ET-3. In the rabbit saphenous vein, it has been shown that ETA1, ETA2, ETB1 and ETB2 receptors mediate contraction. BQ-788 (10 microM) almost completely inhibited the contractile effect of sarafotoxin S6c (an ETB1 and ETB2 agonist). BQ-788 also antagonized the contractile effect of ET-3 (an ETA1, ETB1 and ETB2 agonist) more strongly than desensitization of ETB1 and ETB2 receptors. However, BQ-788 did not antagonize the effect of ET-1 (agonist of all four receptors). In the guinea pig ileum, 10 microM BQ-788 completely inhibited the relaxation mediated by ETB1 and ETB2 receptors. These results suggest that BQ-788 is a novel antagonist of ETB1 and ETB2 receptors with weak antagonistic effect on the ETA1 receptor.