SMOKE-INDUCED AIRWAY HYPERRESPONSIVENESS TO INHALED WOOD SMOKE IN GUINEA-PIGS - TACHYKININERGIC AND CHOLINERGIC MECHANISMS

The smoke-induced airway hyperresponsiveness (SIAHR) to inhaled wood s moke was investigated in anesthetized guinea pigs. Two smoke challenge s teach 10 mi) separated by 30 min were delivered into the lungs by a respirator. In control animals, SIAHR was evidenced by an average bron choconstrictive response tan increase in total lung resistance) to the second smoke challenge (SM2) that was similar to 4.3-fold greater tha n that to the first challenge (SM1). Pretreatment with CP-96,345 and S R-48,968 (neurokinin-l and -2 receptor antagonists; each 1 mg/kg) in c ombination totally prevented this SIAHR, while pretreatment with CP-96 ,344 and SR-48,965 (inactive enantiomers of CP-96,345 and SR-48,968, e ach 1 mg/kg) in combination failed to do so. Pretreatment with CP-96,3 45 (1 mg/kg), SR-48,968 (1 mg/kg), or atropine (50 mu g/kg) significan tly alleviated this SIAHR. Pretreatment with phosphoramidon [an inhibi tor of neutral endopeptidase (NEP); 2 mg/kg], which suppresses the deg radation of tachykinins, induced an increase in airway reactivity that largely mimicked this SIAHR. The NEP activity measured in airway tiss ues excised 30 min after SM1 was significantly lower than that in air control value. These results suggest that 1) a prior wood smoke exposu re induces an airway hyperresponsiveness to the subsequent wood smoke inhalation, 2) a tachykininergic mechanism involving both neurokinin-l and -2 receptors is essential for, and a cholinergic mechanism is als o involved in the development of this SIAHR, and 3) inactivation of ai rway NEP by wood smoke may contribute to this SIAHR.