Studies of nonadrenergic noncholinergic inhibitory (NANCi) nerve-induced relaxations routinely examine relaxations in airway tissue in which tone has been established. Little is known about the ability of NANCi nerve stimulation to prevent airway smooth muscle contraction. The present study compares the capacity of NANCi nerve stimulation to prevent or reverse airway smooth muscle contraction. NANCi nerves in the trachea from ovalbumin-sensitized guinea pigs were subjected to electrical field stimulation (EFS, 10 Hz, 0.3 ms, 10 V, 35 min) initiated before or after induction of tone with antigen or histamine. In tissues precontracted with histamine or antigen, EFS elicited a rapid relaxation which peaked within the first 5 min and stabilized by 20 to 35 min. The peak relaxation was smaller in tissues precontracted with antigen, an effect that was not prevented by tissue treatment with a nitric oxide synthase inhibitor. In contrast, the stabilized level of NANCi relaxation did not differ between histamine- or antigen-contracted tissues. Activation of NANCi nerves prior to induction of tone also resulted in inhibition of the contractile actions of histamine and antigen. However, the stabilized level of tone induced by a contractile agonist added after initiation of EFS was greater than the stabilized tone caused by EFS in tissues already contracted with the same agonist. Relaxations elicited by S-nitrosoglutathione were reduced in antigen-precontracted tissues whereas vasoactive intestinal peptide-induced relaxant responses were similar in antigen- and histamine-precontracted tissues. Results of this study suggest that NANCi nerve activation is more effective at relaxing established airway smooth muscle tone than at preventing airway smooth muscle contraction. Further, the results suggest that the difference in NANCi activity in antigen-precontracted tissues cannot be ascribed solely to reductions in the nitric oxide-dependent component of the response.