The interaction of vagal neuronal and pharmacological mediator mechanisms on the airway-constrictory responses obtained from challenges with aerosolized methacholine (MCH) before and after bilateral vagotomy and in combination with electrical stimulation of the peripheral ends of the cut vagal nerves was investigated in anesthetized Ascaris allergen skin-sensitive sheep. Inhalation of aerosols of 2 and 5% MCH for 2 min in a control group of 10 sheep resulted in airway muscle constriction indicated by an increase in dynamic elastance (Edyn) (+70 and +256% of the basic value) or inspiratory airway resistance (RI) (+45 and +155%) and was associated with a significant rise in plasma histamine concentration (HiP1) from 0.2 ± 0.2 to 0.9 ± 1.1 and 1.5 ± 1.2ng/ml, respectively. Respiratory and cardiovascular responses to MCH were reproducible after 90 min of recovery. A second group of another 6 intact sheep showed similar alterations of respiratory mechanical parameters and HiP1 after MCH challenges. After bilateral vagotomy, Edyn and RI increased after 2 and 5% MCH inhalation only by 15-30% of the control responses with intact vagi. The diminished airway constriction was associated with similar changes in HiPl as observed with intact vagi. Inspite of severe cardiovascular responses, the most effective electrical stimulation of the peripheral ends of the vagal nerves resulted in an increase in Edyn or RI by only 40-50% of the basic value. In a tracheal segment beneath the cuff of the endotracheal tube isometric pressure effectively increased by almost 500% of the basic value. Vagus nerve stimulation was found without detectable changes in HiPl. Stimulation of the central ends of the vagal nerves did not induce airway constriction or alterations in HiPl. The combination of electrical vagus nerve stimulation and MCH inhalation resulted in a more than additive increase in Edyn and RI, but the airway responses did not reach the same level of obstruction after challenge with 5% MCH as observed with intact vagi. Electrical stimulation of the efferent vagi failed to simulate spontaneous vagal nerve activity at higher levels of airway muscle responses. The results demonstrate that vagal neuronal mechanisms interact with local mediator liberation in acute airway obstruction. Airway challenge tests using cholinergic substances liberate histamine from inflammatory cells in the lungs of Ascaris skin-sensitive she