Involvement of Tachykinins in Pentamidine-induced Airway Constriction and Microvascular Leakage in the Guinea Pig

Abstract

We investigated the effects of aerosolized pentamidine isethionate on airway constriction and microvascular leakage in the guinea pig, and the 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 increasing 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 Evans blue dye concentration in the trachea and main bronchi. Aerosolized pentamidine caused a concentration-related increase in respiratory system resistance that was prevented by pretreatment with 50 mg/kg capsaicin given subcutaneously 2 wk before pentamidine and was significantly reduced by pretreatment with 1 mg/kg morphine given intravenously. Pretreatment with 10(-4) M aerosolized phosphoramidon (90 breaths) significantly enhanced the bronchoconstrictor response to pentamidine. Aerosolized pentamidine (50 mg/ml; 90 breaths) increased airway microvascular 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. Pretreatment with 5 mg/ml aerosolized albuterol (90 breaths) prevented the bronchoconstrictor response to pentamidine but failed to prevent the pentamidine-induced increase in microvascular permeability. Atropine did not modify the bronchoconstrictor response to pentamidine. These results indicate that in the guinea pig, pentamidine isethionate induces bronchoconstriction 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 prevent airway edema.