The contribution of the nonadrenergic inhibitory system to airway responses to infusion of 5-hydroxytryptamine (5-HT) was evaluated in anesthetized, tracheotomized, and paralyzed young (13 days) and adult (82 days) guinea pigs. Animals were mechanically ventilated by a constant flow ventilator. Compliance (C) and conductance (G) of the respiratory system were continuously monitored. Three series of experiments were performed involving intravenous pretreatment with 1) atropine (3 mg/kg) and propranolol (1 mg/kg); 2) atropine (3 mg/kg), propranolol (1 mg/kg), and phentolamine (2 mg/kg); and 3) atropine (3 mg/kg) and hexamethonium (2 mg/kg). 5-HT was then intravenously infused for 5 min at a rate of 40 ng.kg-1.s-1 in adults and 60 ng.kg-1.s-1 in young guinea pigs to obtain the same degree of bronchoconstriction in both groups. At the 3rd min of the infusion, bilateral cervical vagotomy was performed and C and G were measured at the maximal response, 1-2 min thereafter. Vagotomy increased bronchoconstriction (P less than 0.01) in both young animals and adults. Phentolamine did not modify this increase, but hexamethonium completely inhibited it. These results indicate that, in adult and young guinea pigs, 5-HT infusion induces reflex activation of the nonadrenergic inhibitory system, which in turn modulates the bronchoconstrictor responses to 5-HT. This neural modulation is not mediated by an alpha-adrenergic pathway.