Exposure to cigarette smoke is associated with increased airway responsiveness to different stimuli, both in human and animal studies. However, the mechanisms involved in the pathogenesis of smoke-induced airway hyperreactivity are less clear. We investigated the development of airway hyperreactivity induced by active cigarette smoke exposure in anaesthetised guinea-pigs and the possible mechanisms involved. Active inhalation of cigarette smoke (15 s/min for 10 min) potentiated the broncho-contractile effect of acetylcholine (Ach), indicating the occurrence of airway hyperreactivity. This phenomenon appeared within 5 min and lasted up to 50 min after smoke exposure. Smoke induced airway hyperreactivity was a non-specific phenomenon, involving an enhanced responsiveness to both Ach and histamine (Hist). Recruitment of proinflammatory cells into the airway lumen, as revealed by the analysis of bronchoalveolar lavage fluid, paralleled the development of the hyperreactive phenomenon, suggesting a relationship between the inflammatory reaction and the genesis of smoke-induced airway hyperreactivity. Cervical bilateral vagotomy did not modify either the degree and the time-course of smoke induced airway hyperreactivity. Moreover, atropine treatment did not affect the increase in Hist response due to smoke inhalation. On the other hand, depletion of substance P due to capsaicin pretreatment almost completely prevented the capacity of cigarette smoke to potentiate Ach induced bronchoconstriction. Cyclo-oxygenase inhibition, by indomethacin pretreatment, reduced the time course of the hyperreactivity induced by smoke inhalation. Our results clearly demonstrate the occurrence of airway hyperreactivity triggered by active cigarette smoke exposure. Moreover, the data obtained suggest a predominant role for substance P and related peptides in the pathogenesis of smoke induced increase in airway responsiveness.