To investigate the role of tachykinins in pentamidine-induced bronchoconstriction and airway microvascular leakage in the guinea pig, we examined the effects on bronchoconstriction and microvascular leakage of the nonpeptide antagonists of NK1 and NK2 tachykinin-receptors, respectively, CP-96,345 and SR 48968. Respiratory system resistance was measured by the occlusion method in anaesthetized, tracheotomized and mechanically 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 abolished pentamidine-induced bronchoconstriction (at 5 to 30 mg/mL pentamidine; 60 breaths) whereas the combination of the two prevented it. In contrast, CP-96,345 and SR 48968 did not prevent the increase in airway microvascular 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, pentamidine-induced bronchoconstriction is mediated through both NK1 and NK2 tachykinin-receptor activation and that when directly administered into the airways, tachykinin antagonists effectively prevent pentamidine-induced bronchoconstriction.