TACHYKININ RECEPTOR ANTAGONISTS INHIBIT HYPERPNEA-INDUCED BRONCHOCONSTRICTION IN GUINEA-PIGS

We tested the hypothesis that hyperpnea-induced bronchoconstriction (H IB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH) ar e mediated through stimulation of NK-1 and NK-2 receptors in guinea pi gs. We first established the efficacy and selectivity of (+/-) CP-96,3 45 (3 mg/kg i.v.) and of SR-48,968 (300 mug/kg i.v.) as NK-1 and NK-2 antagonists, respectively. (+/-) CP-96,345 substantially attenuated br onchoconstriction and systemic vascular leak caused by administration of Sar9, Met(O2)11-Substance P (a specific NK-1 agonist), but had no e ffect upon bronchoconstriction induced by selective NK-2 stimulation w ith Nle10-Neurokinin A[4-10]. Conversely, SR-48,968 antagonized the br onchoconstrictor response to Nle10-NKA[4-10], right-shifting the dose- response curve by 2 log units, but had no effect on Sar9, Met(O2)11-SP -induced bronchoconstriction. Anesthetized, tracheostomized, opened-ch est male Hartley guinea pigs were pretreated with (+/-) CP-96,345 (3 m g/kg i.v.), SR48,968 (300 gg/kg i.v.), or their respective vehicles, a nd Evans blue dye (30 mg/kg i.v.) to label circulating albumin. 10 min isocapnic dry gas hyperpnea (12 ml/kg, 150 breaths/min) provoked HIB and HIBVH in vehicle-treated animals. (+/-) CP-96,345 reduced the magn itude of HIB by one-half (peak posthyperpnea RL 7.8+/-1.9 [SE] times p rehyperpnea baseline versus 16.1+/-2.6, vehicle-treated; P less-than-o r-equal-to 0.0001, ANOVA), SR-48,968 blocked HIB more completely (peak posthyperpnea RL 5.1+/-1.7 [SE] times prehyperpnea baseline versus 19 .3+/-2.8, vehicle-treated; P < 0.0001, ANOVA). Neither drug reduced HI BVH. We conclude that dry gas hyperpnea causes bronchoconstriction in guinea pigs through activation of tachykinin receptors. The differenti al effects of neurokinin receptor blockade on HIB and HIBVH demonstrat e that hyperpnea-induced airflow obstruction is not primarily a conseq uence of hyperpnea-induced bronchovascular leak.