Tachykinin receptor antagonists inhibit hyperpnea-induced bronchoconstriction in guinea pigs (original) (raw)

1993, Journal of Clinical Investigation

We tested the hypothesis that hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH) are mediated through stimulation of NK-1 and NK-2 receptors in guinea pigs. We first established the efficacy and selectivity of (±) CP-96,345 (3 mg/kg i.v.) and of 968 (300 ,ug/kg i.v.) as NK-1 and NK-2 antagonists, respectively. (±) CP-96,345 substantially attenuated bronchoconstriction and systemic vascular leak caused by administration of Sar9, Met(02)"-Substance P (a specific NK-1 agonist), but had no effect upon bronchoconstriction induced by selective NK-2 stimulation with Nle -Neurokinin A14-10I. Conversely, SR-48,968 antagonized the bronchoconstrictor response to Nle'0-NKA14-101, right-shifting the doseresponse curve by 2 log units, but had no effect on Sar9, Met(02)"-SP-induced bronchoconstriction. Anesthetized, tracheostomized, opened-chest male Hartley guinea pigs were pretreated with (±) CP-96,345 (3 mg/kg i.v.), SR48,968 (300 ,ug/kg i.v.), or their respective vehicles, and 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 magnitude of HIB by one-half (peak posthyperpnea RL 7.8±1.9 ISEI times prehyperpnea baseline versus 16.1±2.6, vehicle-treated; P < 0.0001, ANOVA); SR48,968 blocked HIB more completely (peak posthyperpnea RL 5.1±1.7 ISEI times prehyperpnea baseline versus 19.3±2.8, vehicle-treated; P < 0.0001, ANOVA). Neither drug reduced HIBVH. We conclude that dry gas hyperpnea causes bronchoconstriction in guinea pigs through activation of tachykinin receptors. The differential effects of neurokinin receptor blockade on HIB and HIBVH demonstrate that hyperpnea-induced airflow obstruction is not primarily a consequence of hyperpnea-induced bronchovascular leak. (J. Clin. Invest. 1993. 92:315-323.) Key words: exercise-induced asthma-tachykinin * respiratory heat and water loss * bronchovascular hypermeability * C-fiber