Antagonistic effects of FR173657 on human, pig, rabbit, and guinea pig kinin receptors: an in vitro study

The pharmacodynamic features of the new nonpeptide kinin B-2 receptor antagonist FR 173657 were evaluated on pig, rabbit, guinea pig, and human native kinin B-2 receptors. FR 173657 exerted high antagonistic activity in all preparations examined. In particular, it acts as a competitive antagonist in the rabbit jugular vein (pA(2) 8.9) and in the human umbilical vein (pA(2) 8.2) but as a noncompetitive antagonist in the pig coronary artery (pK(B) 9.2) and in the guinea pig ileum (pK(B) 9.2) stimulated with the selective B-2 receptor agonist bradykinin (BK). In contrast, FR 173657 failed to antagonize the biological effects of the selective B-1 receptor agonist LysdesArg(9)BK in the pig renal vein, rabbit aorta, and human umbilical vein, three kinin B-1 receptor systems. Moreover, this compound was inactive against the effects induced by noradrenaline, 5-hydroxytryptamine, endothelin-1, angiotensin II, substance P, acetylcholine, and histamine in the B-2 receptor preparations. Taken together, these results demonstrate that FR 173657 is the first potent nonpeptide B-2 receptor antagonist with high affinity, selectivity, and specificity for kinin B-2 receptors of different species, including man.