Background: Repeated inhalation of bradykinin and hypertonic saline leads to refractoriness of the bronchoconstrictor response in asthma. It is not known whether cross-refractoriness exists between these stimuli. Objective: We postulated that repeated bradykinin and hypertonic saline bronchial challenges might reduce the airway response to subsequent hypertonic saline and bradykinin challenges, respectively. Methods: Eleven atopic asthmatic subjects underwent two concentration-response studies, separated by 1 hour, with either inhaled histamine or bradykinin. After recovery, a hypertonic saline challenge was performed. During the next phase, nine subjects underwent two concentration-response studies, separated by 1 hour, with hypertonic saline. After recovery, a bradykinin challenge was performed. Results: On the histamine study day, the mean provocative volume of agonist required to produce 20% drop in forced expiratory volume in 1 second (PD₂₀) hypertonic saline was 220.7 L (±42.7 L) and this was not significantly different from that measured at baseline. On the bradykinin study day, the geometric mean provocative concentration of agonist required to produce a 20% drop in forced expiratory volume in 1 second (PC₂₀) was 0.39 mg/ml (0.01 to 11.73 mg/ml) for the first test and significantly higher at 1.38 mg/ml (0.01 to >16.0 mg/ml) for the second test (p = 0.006). The hypertonic saline PD₂₀ increased significantly from a baseline of 159.2 L (±27.3 L) to 377.6 (±64.7 L) (p = 0.003). On the hypertonic saline study day, the mean PD₂₀ was 152.8 L for the first test, and 337.7 L for the second test (p = 0.01). PC₂₀ bradykinin increased significantly from a baseline of 0.57 to 2.56 mg/ml (p = 0.02). A significant correlation was found between loss of response to bradykinin and to hypertonic saline (r_s, 0.63 and 0.76). Conclusion: Refractoriness produced by repeated exposure of the airways to bradykinin and hypertonic saline results in loss of responsiveness to hypertonic saline and bradykinin respectively, suggesting a shared mechanism for refractoriness produced by these stimuli. (J Allergy Clin Immunol 1995;96:502-9.)