To investigate the effects of methacholine (MTH) challenge on spirometry, lung mechanics, respiratory gases, and ventilation-perfusion (VA/Q) distributions, 16 subjects 16 to 58 yr of age with stable mild asthma (FEV1, 92 +/- 5% [SEM] predicted; FEF25-75, 71 +/- 7% predicted; respiratory system resistance (Rrs) at 4 Hz, 4.6 +/- 0.4 cm H2O/L-1 s; PaO2, 88 +/- 3 mm Hg; AaPO2, 23 +/- 3 mm Hg) were recruited. Baseline VA/Q distributions were unimodal and relatively narrow in 12 patients and modestly bimodal in the other four. The dispersion of pulmonary blood flow (log SD Q) was slightly enlarged (0.71 +/- 0.09) and that of ventilation (log SD V) was normal (0.57 +/- 0.04) (normal range, 0.3 to 0.6); an index of overall VA/Q heterogeneity (DISP R-E*) was also mildly abnormal (5.3 +/- 0.8) (normal values less than 3.0). After MTH challenge, FEV1, FEF25-75, and PaO2 fell (to 62 +/- 3 and 35 +/- 3% predicted, and to 71 +/- 1 mm Hg, respectively), whereas Rrs (p less than 0.001 each), minute ventilation (p less than 0.02), heart rate (p less than 0.01), and AaPO2 increased (p less than 0.001). VA/Q relationships mildly to moderately worsened (log SD Q increased to 0.98 +/- 0.04 [p less than 0.01], log SD V to 0.79 +/- 0.04, and DISP R-E* to 9.8 +/- 0.6 [p less than 0.001 each]). Qualitatively, the pattern of blood flow distribution was broadly unimodal in 13 patients and modestly bimodal in three, of whom only one had a bimodal baseline distribution.(ABSTRACT TRUNCATED AT 250 WORDS)