EFFECT OF MDL-105,212, A NONPEPTIDE NK-1 NK-2 RECEPTOR ANTAGONIST IN AN ALLERGIC GUINEA-PIG MODEL/

MDL 105,212 has been identified as a potent, nonpeptide NK-1 and NK-2 receptor antagonist that inhibits effects of substance P and neurokini n A in vitro and in vivo (Kudlacz el al., 1996). In the present study, the compound inhibited capsaicin-induced respiratory effects after p. o. administration (5-50 mg/kg) to conscious guinea pigs; nearly comple te inhibition of dyspnea and cough was observed 1 hr after 50 mg/kg p. o., and efficacy persisted for approximately 11 hr. MDL 105,212 reduce d pulmonary insufflation pressure and microvascular leakage in ovalbum in-sensitized animals in response to antigen-challenge relative to veh icle-treated animals. Attenuation of early-phase allergic responses ma y result from MDL 105,212 inhibition of antigen-induced histamine rele ase from sensitized guinea pig lung observed in vitro. Airway hyperres ponsiveness to methacholine occurred 24 hr after antigen-challenge in ovalbumin-sensitized guinea pigs; this effect was inhibited by pretrea tment with MDL 105,212 (50 mg/kg p.o.) 1 hr before ovalbumin exposure without affecting increased bronchoalveolar lavage eosinophil numbers. These data suggest that. sensory neuropeptides play a role in some as pects of allergic airway responses and that tachykinin receptor antago nists may be useful in treatment of atopic respiratory diseases.