We investigated whether the plateau of the dose-response to nonsensitizing stimuli, such as methacholine, could be explained by the airway dilation that follows lung inflation in nonasthmatics. We used maximal expiratory partial flow-volume curves to measure the response of the airways to doubling doses of inhaled methacholine up to 256 mg/ml (a noncumulative dose of 340 mumol delivered to the mouth during tidal breathing) in 12 nonasthmatics on 2 days. Maximal expiratory complete flow-volume curves and FEV1 were also obtained along with the partial curves. Flows were measured at 40% of control vital capacity using the complete (V40c) and the partial (V40p) curves. A maximal response plateau of 2 or more doubling concentrations was demonstrated in all subjects based on V40p, and in 10 subjects based on FEV1. The level of the plateau was the highest for the V40p (mean +/- SD = 65 +/- 19% of baseline), intermediate for V40c (45 +/- 22%), and the lowest for FEV1 (16 +/- 11%). There was more than a 100-fold range in responsiveness expressed as the provocative concentration to cause a 40% fall of baseline in V40p (PC40); the lower the PC40, the higher the level of the plateau. All the results were reproducible between the 2 days. We also investigated whether the plateau may have been due to a tachyphylactic effect of cumulative doses of methacholine. The maximal response after increasing concentrations of methacholine up to 256 mg/ml was not different from the response obtained after a single dose of 256 mg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)