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

1 We examined the effects of phosphonium, [[4-[[2-[[bis(cyclohexylamino)methylene] amino]-3-(2-naphthalenyl) 1-oxopropyl]amino]-phenyl]-tributyl, chloride, monohydrochloride (WIN 64338), a novel, nonpeptide bradykinin Bz receptor antagonist, on bradykinin-induced contractions of guinea-pig isolated ileum, and guinea-pig and ferret trachea. 2 WIN 64338 potently and competitively antagonized ileal contractions, in response to bradykinin, exhibiting a pA(2) value of 7.97 +/- 0.10. The compound was without effect on contractions elicited by methacholine, a muscarinic receptor antagonist. Thus, WIN 64338 is a competitive and selective antagonist of ileal B-2 receptors. 3 In contrast, WIN 64338 was completely without effect on bradykinin-induced contractions of guineapig or ferret trachea. Thus, even at a concentration of 1 mu M, which 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 antagonist of guinea-pig ileal B-2 receptors. They also provide additional evidence for heterogeneity of bradykinin receptors within the same species (guinea-pig) and, furthermore, indicate that the tracheal bradykinin receptor (B-3?) is different from that in deal tissue (B-2).