AEROSOLIZED TACHYKININ ANTAGONISTS INHIBIT PENTAMIDINE-INDUCED BRONCHOCONSTRICTION IN GUINEA-PIGS

To investigate the role of tachykinins in pentamidine-induced bronchoc onstriction and airway microvascular leakage in the guinea pig, we exa mined the effects on bronchoconstriction and microvascular leakage of the nonpeptide antagonists of NK1 and NK2 tachykinin-receptors, respec tively, CP-96,345 and SR 48968. Respiratory system resistance was meas ured by the occlusion method in anaesthetized, tracheotomized and mech anically ventilated guinea pigs. Airway microvascular permeability was evaluated by measuring the quantity of Evans blue dye in the trachea and main bronchi. Aerosolized CP-96,345 or SR 48968 partially abolishe d pentamidine-induced bronchoconstriction (at 5 to 30 mg/mL pentamidin e; 60 breaths) whereas the combination of the two prevented it. fn con trast, CP-96,345 and SR 48968 did not prevent the increase in airway m icrovascular permeability induced by pentamidine (50 mg/mL; 90 breaths ) whether they were administered separately or together, by aerosol or intravenously. These results demonstrate that in the guinea pig, pent amidine-induced bronchoconstriction is mediated through both NK1 and N K2 tachykinin-receptor activation and that when directly administered into the airways, tachykinin antagonists effectively prevent pentamidi ne-induced bronchoconstriction.