A ROLE FOR HISTAMINE AND SUBSTANCE-P IN IMMEDIATE ALLERGIC RESPONSES IN GUINEA-PIG AIRWAYS - CHARACTERIZATION OF MDL-108,207DA, A DUAL H-1 NK-1 RECEPTOR ANTAGONIST/

Background: Histamine is a critical mediator of immediate hypersensiti vity reactions. Sensory neuropeptides, such as substance P (SP), may a lso contribute to acute inflammatory responses. A compound which antag onizes both H-1 and NK-1 receptors, such as MDL 108,207DA, may present a significant therapeutic advantage over pure antihistamines. Methods : The binding affinity of MDL 108,207DA for H-1 and NK-1 receptors was evaluated and its potency of antagonism evaluated in vitro. The in vi vo antagonism of SP- or histamine-induced microvascular leakage in gui nea pig airways was examined. A role for these mediators in antigen-in duced microvascular leakage in ovalbumin-sensitized guinea pig airways was examined using MDL 108,207DA as well as the NK-1-selective antago nist FK888 and the H-1-selective antagonist pyrilamine alone or in com bination. Results: The affinity of MDL 108,207DA for H-1 and NK-1 rece ptors is similar to that of receptor-selective antagonists. The compou nd inhibits both receptors in vitro and in vivo with comparable potenc ies for each. The efficacy of FK888 in combination with pyrilamine and MDL 108,207DA on antigen-induced microvascular leakage in sensitized guinea pig airways supports a role for both SP and histamine in early allergic responses. Conclusion: The contribution of both SP and histam ine to immediate hypersensitivity reactions supports the utility of NK -1 and H-1 receptor antagonist therapy. MDL 108,207DA incorporates bot h activities into the same compound and, as a result, may be useful in the treatment of allergic diseases.