title: Competitive and selective antagonistic action of NPC 17731 on bradykinin-induced relaxant and contractile responses of the guinea pig isolated ileum.
abstract: 1. The aim of the present study was to evaluate, by means of functional studies, the effect of the newly developed bradykinin (BK) receptor antagonist NPC 17731, D-Arg0, Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-[DHype (transpropyl)7]-Oic8-Arg9, against BK-mediated biphasic response in the guinea pig ileum "in vitro" (circular and longitudinal layers). 2. In the circular muscle, NPC 17731 (0.1-1000 nM) dose dependently and reversibly antagonized, with similar potency, both the contractile and relaxant responses caused by BK, as well as BK-induced contraction in longitudinal smooth muscle with IC50 of 23, 29 and 37 nM, respectively. 3. NPC 17731 (10-300 nM) also caused a concentration-dependent displacement to the right of BK-induced contraction and relaxant responses in the circular smooth muscle of guinea pig ileum, without changing BK maximal response. Schild plot analyses were linear (correlation close to 1), yielding pKb values of 8.89 +/- 0.19 and 8.73 +/- 0.18, respectively, and slopes not significantly different from unity, providing evidence that NPC 17731 acts as a pure B2 competitive receptor antagonist against both BK responses. 4. Similarly, NPC 17731 (3-100 nM) antagonized, in a graded and competitive manner, BK-induced contraction in longitudinal muscle from guinea pig ileum with a slope not different from unity, yielding a pKb value of 8.62 +/- 0.13. 5. These results indicate that the new B2 BK receptor antagonist NPC 17731 antagonizes, with high affinity and with similar potency through simple competitive and selective mechanisms, BK receptor-mediating contraction or relaxant responses in circular and longitudinal smooth muscles from guinea pig ileum. In addition, these results also suggest that although BK-induced contraction or relaxation responses in guinea pig ileum are coupled to distinct second messengers, NPC 17731 interacts with a homogeneous population of B2 receptors in both guinea pig ileum preparations.
authors.affiliation: Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
authors.forename: Y S
authors.initials: YS
authors.lastname: Medeiros
authors.forename: J B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors*; D005260:Female; D006168:Guinea Pigs; D007082:Ileum; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology*
chemical_list: D009842:Oligopeptides; C071327:NPC 17731; D001920:Bradykinin