title: Effects of an NK1 receptor antagonist, FK888, on constriction and plasma extravasation induced in guinea pig airway by neurokinins and capsaicin.
abstract: The effects of FK888, an NK1 receptor antagonist, on airway constriction and airway plasma extravasation induced by neurokinins and capsaicin were investigated in guinea pigs. FK888 inhibited substance P (10(-8) M)- and neurokinin A (10(-9) M)-induced contraction of isolated guinea pig trachea, with IC50 values of 3.2 x 10(-8) and 4.2 x 10(-6) M, respectively. FK888 given i.v. inhibited substance P (13.5 micrograms kg-1)-induced airway constriction with an ED50 value of 0.40 mg kg-1 but did not inhibit neurokinin A (1.1 micrograms kg-1)- and capsaicin (3.1 micrograms kg-1)-induced airway constriction at a dose of 1 mg kg-1. On the other hand, FK888 given i.v. inhibited airway plasma extravasation induced by substance P (1.3 micrograms kg-1), neurokinin A (11 micrograms kg-1) and capsaicin (100 micrograms kg-1) with equal potency and ED50 values of 0.011, 0.0063 and 0.019 mg kg-1, respectively. When FK888 was given locally (into the airway directly) inhibitory activities were more potent than following i.v. administration. In this case FK888 inhibited substance P-, neurokinin A- and capsaicin-induced airway constriction with ED50 values of 3.2, 190 and 550 micrograms kg-1, respectively, suggesting that an about 100 times higher dose is required to inhibit neurokinin A- and capsaicin-induced airway constriction than substance P-induced constriction. FK888 given orally was also effective in substance P-, neurokinin A- and capsaicin-induced airway plasma extravasation with ED50 values of 4.2, 5.9 and 9.5 mg kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Murai
authors.forename: Y
authors.initials: Y
authors.lastname: Maeda
authors.forename: D
authors.initials: D
authors.lastname: Hagiwara
authors.forename: H
authors.initials: H
authors.lastname: Miyake
authors.forename: N
authors.initials: N
authors.lastname: Ikari
authors.forename: M
authors.initials: M
authors.lastname: Matsuo
authors.forename: T
authors.initials: T
authors.lastname: Fujii
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002211:Capsaicin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D015288:Neurokinin A / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology
chemical_list: D004151:Dipeptides; D007211:Indoles; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; C078949:FK 888; D013373:Substance P; D015288:Neurokinin A; D002211:Capsaicin