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-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, ET(B1) receptor-mediated relaxation due to endothelin (ET)-3 with EC(50) of 3 mu M. In the rat aorta without endothelium, 10 mu M 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 mu M) 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 mu M 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. (C) 1994 Academic Press, Inc.