Effect of SR 140333, a selective NK1 antagonist, on antigen-induced oedema formation in rat skin

SR 140333, the first member of a newly developed neurokinin-1 (NK1) receptor antagonist series, inhibited in a dose-dependent manner oedema formation in rat skin when administered i.d. premixed with [Arg6,Sar9,Met(O2)11]substance P(6-11) (NK1 ago), a selective agonist of the NK1 receptor or substance P (SP) (ED50 values = 0.9 +/- 0.3 and 0.8 +/- 0.2 nmol/site, respectively) (n = 9). SR 140333 protected rats from NK1 ago- or SP-induced plasma extravasation with ED50 values of 35 +/- 7 and 43 +/- 6 micrograms/kg, respectively, when given i.v. 15 min before the challenge. In ovalbumin-presensitized rats, SR 140333, premixed with the allergen, inhibited in a dose-dependent manner plasma exudation (ED50 = 0.18 +/- 0.04 nmol/site, i.d.) (n = 15). Intravenous injection of SR 140333 inhibited allergen-induced vascular permeability (ED50 = 87 +/- 14 micrograms/kg). These results therefore show that NK1 plays a major role in the development of cutaneous anaphylaxis and that SR 140333 may be an effective prophylactic drug.