INVOLVEMENT OF TACHYKININS IN PENTAMIDINE-INDUCED AIRWAY CONSTRICTIONAND MICROVASCULAR LEAKAGE IN THE GUINEA-PIG

We investigated the effects of aerosolized pentamidine isethionate on airway constriction and microvascular leakage in the guinea pig, and t he role of tachykinins in these abnormalities. The bronchoconstrictor response to pentamidine was determined in anesthetized, tracheotomized and mechanically ventilated guinea pigs by exposing them to increasin g concentrations of aerosolized pentamidine (5 to 30 mg/ml; 60 breaths ). Respiratory system resistance was measured by the occlusion method. Airway microvascular permeability was evaluated by measuring the Evan s blue dye concentration in the trachea and main bronchi. Aerosolized pentamidine caused a concentration-related increase in respiratory sys tem resistance that was prevented by pretreatment with 50 mg/kg capsai cin given subcutaneously 2 wk before pentamidine and was significantly reduced by pretreatment with 1 mg/kg morphine given intravenously. Pr etreatment with 10(-4) M aerosolized phosphoramidon (90 breaths) signi ficantly enhanced the bronchoconstrictor response to pentamidine. Aero solized pentamidine (50 mg/ml; 90 breaths) increased airway microvascu lar permeability, as the Evans blue dye concentration was 72.6 +/- 3.7 ng/mg tissue in guinea pigs aerosolized with pentamidine versus 34.2 +/- 3.5 ng/mg tissue in the controls. Capsaicin pretreatment inhibited the increase in microvascular leakage induced by pentamidine. Pretrea tment with 5 mg/ml aerosolized albuterol (90 breaths) prevented the br onchoconstrictor response to pentamidine but failed to prevent the pen tamidine-induced increase in microvascular permeability. Atropine did not modify the bronchoconstrictor response to pentamidine. These resul ts indicate that in the guinea pig, pentamidine isethionate induces br onchoconstriction and airway microvascular leakage, which are mediated by tachykinins released from sensory nerves. Albuterol, which is used in humans to prevent bronchoconstriction, does not seem able to preve nt airway edema.