We investigated the hypothesis that airway M2-receptor selectively pretreated with aerosolized pilocarpine would modify the bronchoconstrictor response to histamine, which is, in part, vagally mediated. On two different days, the following two histamine inhalation challenges were performed in 12 normal individuals and 13 stable asthmatics: histamine alone or pilocarpine-histamine. In normal subjects, prior M2-receptor stimulation with pilocarpine suppressed the subsequent bronchial response to histamine. In asthmatic patients, however, prior pilocarpine exposure failed to modify the bronchial response to histamine. The results suggest that prior M2-receptor stimulation has a protective effect on histamine induced bronchoconstriction in normal subjects and the absence of this inhibitory effect in asthmatic patients may represent the existence of functional depression of M2-receptors in asthmatic airways.