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 NK 1 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 IC 50 values of 3.2 × 10 −8 and 4.2 × 10 −6 M, respectively. FK888 given i.v. inhibited substance P (13.5 μg kg −1 )-induced airway constriction with an ED 50 value of 0.40 mg kg −1 but did not inhibit neurokinin A (1.1 μg kg −1 )- and capsaicin (3.1 μg 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 μg kg −1 ), neurokinin A (11 μg kg −1 ) and capsaicin (100 μg kg −1 ) with equal potency and ED 50 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 ED 50 values of 3.2, 190 and 550 μg kg −1 , respectively, suggesting that an about 100 times higher dose is reguired 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 ED 50 values of 4.2, 5.9 and 9.5 mg kg −1 . These results demonstrate that FK888 is an effective in vivo NK 1 receptor antagonist and the different inhibitory activity of FK888 on airway responses suggests that substance P-, neurokinin A- and capsaicin-induced airway plasma extravasation is solely mediated via NK 1 receptors whereas in airway constriction only substance P-induced reaction is mediated via NK 1 receptors.