Thickening of the airway wall has been hypothesized to be one of the mechanisms contributing to airway hyperresponsiveness in asthma. If such thickening of the wall is internal to the airway smooth muscle or otherwise causes a decrease in baseline airway caliber, it should also cause exaggerated airway responsiveness. In the present study, we used high-resolution computed tomography to directly measure the changes in the caliber and wall thickness of conducting airways after aerosol histamine challenge before and after normal saline volume loading. On separate days, five anesthetized dogs received either a baseline aerosol challenge of 3 mg/ml of histamine for five breaths or the same aerosol challenge immediately after a 100 ml/kg bolus of normal saline infused over a 10-min period. Baseline aerosol histamine challenge decreased airway area to 71 +/- 2% (SE) of the control value (P < 0.05). Intravenous administration of 100 ml/kg of normal saline increased wall area by decreasing airway luminal area to 78 +/- 3% of the control value (P < 0.01), with no change in outer airway area. Aerosol histamine challenge superimposed on this engorgement with normal saline challenge further decreased airway luminal area to 54 +/- 3% of the control value (P < 0.01). Quantitative modeling indicated that the edema in the airway wall was mostly outside the smooth muscle and that the smooth muscle shortening with histamine was similar with and without edema. We conclude that a moderate degree of acute airway wall thickening can lead to a potentiated constrictor response to histamine.