NK₁ Receptor Antagonist CP-99,994 Inhibits Cigarette Smoke-Induced Neutrophil and Eosinophil Adhesion in Rat Tracheal Venules

Abstract

The involvement of neurokinin NK₁ receptors in cigarette smoke-induced adhesion of neutrophils and eosinophils to venules of the airway mucosa was investigated. Rats were pretreated with the NK₁ receptor antagonist CP-99,994 (4mg/kg IV), its vehicle, or its inactive enantiomer CP-100,263 before exposure to cigarette smoke. Adherent neutrophils and eosinophils were stained histochemically for endogenous peroxidase activity and were counted in tracheal whole mounts. Plasma leakage was quantified be stereological measurements of the extravasation of Monastral blue. Cigarette smoke induced the adhesion of 104 + 17 neutrophils and 10.4 ± 1.7 eosinophils per square millimeter of mucosa. CP-99,994 reduced neutrophil and eosinophil adhesion by 66 and 61%, respectively, and reduced plasma extravasation by 617c (p < .05), but CP-100,263 had no significant effect. The inhibitory effects of CP-99,994 appeared to be specific because CP-99,994 had no effect on neutrophil and eosinophil adhesion, or on plasma extravasation induced by platelet activating factor, an inflammatory stimulus acting independently of NK, receptors. These results suggest that NK, receptors are involved in cigarette smoke-induced adhesion of neutrophils and eosinophils to the endothelium of venules in the rat tracheal mucosa.

Key Words:

• endothelium
• neurogenic inflammation
• plasma extravasation
• sensory nerves
• substance P
• tachykinin