EFFECTS OF A NOVEL NONPEPTIDE BRADYKININ B-2 RECEPTOR ANTAGONIST ON INTESTINAL AND AIRWAY SMOOTH-MUSCLE - FURTHER EVIDENCE FOR THE TRACHEALB-3 RECEPTOR

1 We examined the effects of phosphonium, [[4-[[2-[[bis(cyclohexylamin o)methylene] amino]-3-(2-naphthalenyl) 1-oxopropyl]amino]-phenyl]-trib utyl, chloride, monohydrochloride (WIN 64338), a novel, nonpeptide bra dykinin Bz receptor antagonist, on bradykinin-induced contractions of guinea-pig isolated ileum, and guinea-pig and ferret trachea. 2 WIN 64 338 potently and competitively antagonized ileal contractions, in resp onse to bradykinin, exhibiting a pA(2) value of 7.97 +/- 0.10. The com pound was without effect on contractions elicited by methacholine, a m uscarinic receptor antagonist. Thus, WIN 64338 is a competitive and se lective antagonist of ileal B-2 receptors. 3 In contrast, WIN 64338 wa s completely without effect on bradykinin-induced contractions of guin eapig or ferret trachea. Thus, even at a concentration of 1 mu M, whic h was sufficient to cause a 100 fold decrease in ileal sensitivity to bradykinin, WIN 64338 failed to shift the bradykinin log concentration -response curves in trachea isolated from either species. 4 These data confirm that WIN 64338 represents the first reported nonpeptide antag onist of guinea-pig ileal B-2 receptors. They also provide additional evidence for heterogeneity of bradykinin receptors within the same spe cies (guinea-pig) and, furthermore, indicate that the tracheal bradyki nin receptor (B-3?) is different from that in deal tissue (B-2).