We tested the hypothesis that the regular inhalation of a beta 2-adrenergic receptor (beta 2AR) agonist increases airway responsiveness in guinea pigs. A potent beta 2AR agonist, fenoterol hydrobromide, in sublaryngeal doses equivalent to maximal doses used in the treatment of asthma on a weight basis (5.28 micrograms/kg), was administered by nebulizer three times a day for 6 weeks to normal adolescent guinea pigs (FEN, n = 10) and to ovalbuminsensitized guinea pigs challenged twice weekly with ovalbumin (OA + FEN, n = 20), although not in the 12 h prior to or 4 h after antigen challenge. Controls included saline-treated normal animals (CON, n = 10) and ovalbumin-sensitized animals treated with repeated antigen challenge and saline (OA, n = 20). At 72 h after the last administration of saline, fenoterol, and ovalbumin, the dose-response relationship between pulmonary resistance (RL) and nebulized acetylcholine (ACh) was measured. RLmax increased 2-fold and the ACh concentration causing a 10-fold increase in RL (PC10) decreased 4-fold in the FEN, OA, and OA + FEN groups as compared to the CON group. In the FEN, OA, and OA + FEN groups, in vitro tracheal smooth-muscle contractile responses to maximal concentrations of acetylcholine increased 2-fold, and this increase was not due to increased smooth-muscle mass. There was no evidence for beta 2AR desensitization as judged by in vitro tracheal smooth-muscle relaxant responses to fenoterol. These results suggest that chronic beta 2AR stimulation increases airway smooth-muscle contractility and in vivo airways responsiveness to a degree similar to that induced by chronic antigen exposure. A similar effect in human asthmatics may explain the adverse effects observed during prolonged treatment with these drugs.