To explore the role of airway innervation as a determinant of airway responsiveness to inhaled cholinergic agonists, we studied the effects of partial or complete section of the cervical vagosympathetic trunk on the magnitude of methacholine-induced bronchoconstriction in the chloralose-urethane-anesthetized, mechanically ventilated cat. An initial concentration-response curve to methacholine was constructed to identify the concentration required to cause a twofold to threefold rise in mean pulmonary resistance (RL). Using this concentration, 3 consecutive challenges (C1, C2, and C3) were then performed at 30-min intervals in 4 groups of cats. After a control challenge (C1), the parasympathetic (n = 9), sympathetic (n = 6), or both branches (n = 4) of the cervical vagosympathetic trunks were sectioned. Sham cats (n = 7) showed reproducible increases in RL (C1, delta RL = 15.1 +/- 2.7 cm H2O X 1(-1) X s; C2, delta RL = 15.7 +/- 3.0; C3, delta RL = 13.1 +/- 2.9; mean +/- 1 SE). After parasympathectomy there was an increase in responsiveness after C3 (C1, delta RL = 15.0 +/- 4.3; C2, delta RL = 16.4 +/- 6.4; C3, delta RL = 29.9 +/- 11.6; p less than 0.01). Sympathectomy and vagosympathectomy did not significantly alter responsiveness. The results suggest that vagally mediated inhibitory influences modulate the bronchial response to aerosolized methacholine in the cat.