To dissociate airway stimulation from airway response, a segment of the cervical trachea was isolated from the rest of the bronchial tree in 15 anesthetized dogs; nerve and blood supplies of the segment were preserved. Patency of the intrathoracic airways was assessed with lung resistance (RL) measurements. When doses of aerosolized histamine (His), acetylcholine (ACh) and serotonin (Ser) causing comparable increases in RL were delivered into the intrathoracic airways, concomitant increases in pressure were recorded in the tracheal segment (indicating constriction) with His being the most effective. When the hypoxemia accompanying His- and ACh-induced bronchoconstriction was prevented by inhaling an air-oxygen mixture, the tracheal response persisted (2 dogs). Vagotomy decreased the RL response to His, ACh and Ser and abolished tracheal response (13 dogs). The tracheal response was still abolished when larger doses of His and ACh were given in order to induce an increase in RL similar to that observed before vagotomy (7 dogs). These data suggest the existence of a positive feed-back mechanism in the airways, pharmacological bronchoconstriction causing vagally mediated reflex bronchoconstriction. Direct stimulation of lung irritant receptors by histamine may explain the larger degree of reflex bronchoconstriction observed with this agent.