title: Effects of a novel nonpeptide bradykinin B2 receptor antagonist on intestinal and airway smooth muscle: further evidence for the tracheal B3 receptor.
abstract: 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 B2 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 pA2 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 B2 receptors. 3. In contrast, WIN 64338 was completely without effect on bradykinin-induced contractions of guinea-pig or ferret trachea. Thus, even at a concentration of 1 microM, 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 B2 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 (B3?) is different from that in ileal tissue (B2).
authors.affiliation: ZENECA Pharmaceuticals Group, Wilmington, DE 19897-2300.
authors.forename: S G
authors.initials: SG
authors.lastname: Farmer
authors.forename: M A
authors.initials: MA
authors.lastname: DeSiato
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D005289:Ferrets; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
chemical_list: D065168:Bradykinin Receptor Antagonists; D008688:Methacholine Compounds; D009281:Naphthalenes; D009943:Organophosphorus Compounds; C087374:WIN 64338; D001920:Bradykinin