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 hu man native kinin B-2 receptors. FR 173657 exerted high antagonistic ac tivity in all preparations examined. In particular, it acts as a compe titive antagonist in the rabbit jugular vein (pA(2) 8.9) and in the hu man umbilical vein (pA(2) 8.2) but as a noncompetitive antagonist in t he 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 ind uced by noradrenaline, 5-hydroxytryptamine, endothelin-1, angiotensin II, substance P, acetylcholine, and histamine in the B-2 receptor prep arations. 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 sp ecies, including man.