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 constricti on and airway plasma extravasation induced by neurokinins and capsaici n were investigated in guinea pigs. FK888 inhibited substance P (10(-8 ) M)- and neurokinin A (10(-9) M)-induced contraction of isolated guin ea pig trachea, with IC50 values of 3.2 x 10(-8) and 4.2 x 10(-6) M, r espectively. FK888 given i.v. inhibited substance P (13.5 mug kg-1)-in duced airway constriction with an ED50 value of 0.40 mg kg-1 but did n ot inhibit neurokinin A (1.1 mug kg-1)- and capsaicin (3.1 mug kg-1)-i nduced airway constriction at a dose of 1 mg kg-1. On the other hand, FK888 given i.v. inhibited airway plasma extravasation induced by subs tance P (1.3 mug kg-1), neurokinin A (11 mug kg-1) and capsaicin (100 mug kg-1) with equal potency and ED50 values of 0.011, 0.0063 and 0.01 9 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 mug kg-1, respectively, suggesting that an about 100 times higher dose is required to inhibit neurokinin A- and capsaicin-induce d airway constriction than substance P-induced constriction. FK888 giv en orally was also effective in substance P-, neurokinin A-and capsaic in-induced airway plasma extravasation with ED50 values of 4.2, 5.9 an d 9.5 mg kg-1. These results demonstrate that FK888 is an effective in vivo NK1 receptor antagonist and the different inhibitory activity of FK888 on airway responses suggests that substance P-, neurokinin A- a nd capsaicin-induced airway plasma extravasation is solely mediated vi a NK1 receptors whereas in airway constriction only substance P-induce d reaction is mediated via NK1 receptors.