The effects of NK1 receptor antagonists (FK224 and FK888) on agonist- and antigen-induced nasal microvascular leakage in guinea pigs.

Abstract

To study the inhibitory effects of two NK1 receptor antagonists on substance P (SP) and antigen-induced increase of nasal vascular permeability in ovalbumen (OA)-sensitized guinea pigs. Male Dunkin-Hartley guinea pigs. SP (100 mumol/l), FK224 (1-10 mumol/kg) and FK888 (0.2-2 mumol/kg). The in vivo model of nasal microvascular leakage was used for nasal allergic challenge in ovalbumin (OA)-sensitized guinea pigs, or nasal stimulation with substance P (SP) in non-sensitized animals. Nasal microvascular leakage was measured by the accumulation of Evans Blue dye after intravenous injection. Following nasal stimulation with SP 100 microM, the concentration of dye in the nasal lavage fluid rapidly increased. NK1 receptor antagonists FK224 (10 mumol/kg i.v.) and FK888 (2 mumol/kg i.v.) inhibited SP-induced microvascular leakage. In OA-sensitized guinea pigs, exudation of dye into nasal lavage fluid was observed soon after topical antigenic stimulation and continued for over 60 min. Both NK1 receptor antagonists inhibited the immediate phase of the antigen-induced microvascular leakage. We conclude that the immediate change of vascular permeability during the nasal allergic response is mediated by activation of the NK1 receptor in the guinea-pig.