Effects of an NK1 receptor antagonist, FK888, on constriction and plasma extravasation induced in guinea pig airway by neurokinins and capsaicin.
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)
Murai
M
M
Department of Pharmacology, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Maeda
Y
Y
Hagiwara
D
D
Miyake
H
H
Ikari
N
N
Matsuo
M
M
Fujii
T
T
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
D004151:Dipeptides; D007211:Indoles; D018041:Receptors, Neurokinin-2; D017981:Receptors, Neurotransmitter; C078949:FK 888; D013373:Substance P; D015288:Neurokinin A; D002211:Capsaicin