A NEW NK1 RECEPTOR ANTAGONIST (CP-99,994) PREVENTS THE INCREASE IN TRACHEAL VASCULAR-PERMEABILITY PRODUCED BY HYPERTONIC SALINE

The increase in tracheal vascular permeability evoked by hypertonic sa line depends on capsaicin-sensitive sensory nerves, which contain subs tance P and other neuropeptides. The present study was performed to de termine whether a novel, nonpeptide, selective antagonist of the NK1 t achykinin receptor CP-99,994, -3S)-3-(2-methoxybenzylamino)-2-phenylpi peridine], can prevent the effect of substance P, capsaicin and hypert onic saline on tracheal vascular permeability. CP-99,994 was also test ed against a nonpeptide inflammatory mediator, platelet-activating fac tor (PAF), to assess the selectivity of its action. Anesthetized F-344 rats were injected with either substance P (5 mug/kg i.v.), capsaicin (100 mug/kg i.v.) or PAF (10 mug/kg i.v.), or were exposed to ultraso nically nebulized 3.6% NaCl. In each group, some of the rats were pret reated with CP-99,994 (1 to 4 mg/kg i.v.), and some with its vehicle ( 0.9% NaCl). Groups of rats injected with substance P or exposed to hyp ertonic saline were pretreated with the (2R, 3R)-enantiomer CP-100,263 , -3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine], (2 or 4 mg/kg i.v .). The magnitude of the increase in tracheal vascular permeability wa s measured by quantifying the extravasation of Evans blue dye. CP-99,9 94 prevented the increase in tracheal vascular permeability produced b y inhalation of hypertonic saline, by substance P and by capsaicin, bu t did not prevent the effect of PAF. CP-100,263 did not affect substan ce P- and hypertonic saline-induced increase in vascular permeability. These results indicate that the NK, receptor antagonist CP-99,994 pro duces stereoselective inhibition of neurogenic plasma extravasation ev oked by inhalation of hypertonic saline.