We postulated that prolonged exposure to intermittent positive-pressure ventilation (IPPV) with high pressure (HIPPV) alone without hyperoxia promotes the development of airway hyperresponsiveness and remodeling. To test this hypothesis, young rats were ventilated under halothane anesthesia with HIPPV (maximum inspiratory pressure at 32-35 cmH₂O in 70% nitrous oxide and 30% O₂) for 3.5-4 h daily for 6 days. Control rats were ventilated with low IPPV (maximum inspiratory pressure < 13 cmH₂O) during the same time period with the same gas mixture. With the use of tracheal rings isolated from these rats and a setup in tissue baths, contractile responses to carbachol (10⁶ to 10² mM), 5-hydroxytryptamine (5-HT; 10⁹ to 10⁵ mM) and KCl (1-100 mM) were examined isometrically. In tracheal rings from HIPPV rats compared with low-pressure IPPV rats, the concentration tension curves showed a significantly enhanced response to all agonists (P < 0.005). Sensitivity to carbachol, 5-HT, and KCl was also significantly increased (P < 0.05) compared with control rats as evidenced by decreases in EC₅₀. Maximum tension (reactivity) to 5-HT and KCl in the HIPPV group increased significantly (P < 0.05), and there was a trend (P = 0.07) toward increased reactivity to carbachol in this group as well. Histological examinations of tracheal rings demonstrated epithelial squamous metaplasia in the HIPPV group. Morphometric studies demonstrated tracheal smooth muscle thickening (P < 0.05) without changes in the thickness of the mucosa or the lamina propria. When contractile responses were normalized for the smooth muscle cross-sectional area (i.e., stress), reactivity to all contractile agents was reduced, whereas reactivity to 5-HT still demonstrated significant increase (P < 0.005). Sensitivity of tracheal segments to all three agents was not affected by this normalization. These findings suggest that prolonged exposure to HIPPV without hyperoxia and the resultant overdistension of lung tissues (volutrauma) induced airway remodeling and airway hyperreactivity.