Effects of the tripeptide substance P antagonist, FR113680, on airway constriction and airway edema induced by neurokinins in guinea-pigs

Abstract FR113680 is a newly developed tripeptide substance P (SP) receptor antagonist. The effects of FR113680 on airway constriction and airway edema induced by neurokinins were investigated in guinea-pigs. In in vitro experiments, FR113680 inhibited the contraction of isolated guinea-pig trachea induced by SP and neurokinin A (NKA) in a dose-dependent manner with IC 50 values of 2.3 × 10 −6 and 1.5 × 10 −5 M, respectively. The tracheal contraction induced by histamine and acetylcholine was not affected by FR113680. FR113680 (5 × 10 −5 M) also significantly inhibited the atropine-resistant contraction of isolated guinea-pig bronchi induced by electrical field stimulation. In in vivo experiments, FR113680 given i.v. inhibited SP-induced airway constriction in guinea-pigs at doses of 1 and 10 mg kg −1 . However, FR113680 only inhibited NKA- and capsaicin-induced airway constriction by 40–50% even at a dose of 10 mg kg −1 . FR113680 also inhibited SP-induced airway edema in guinea-pigs with the same potency as it inhibited SP-induced airway constriction. Histamine-induced airway constriction and airway edema were not affected at a dose of 10 mg kg −1 . These results suggest that FR113680 preferentially inhibits responses induced by NK 1 receptor activation (SP-induced airway constriction and airway edema), but is less effective on a NK 2 receptor-induced response (airway constriction by NKA and neurogenic stimulation).