The mechanism of refractoriness in bronchoconstriction after repeated hyperventilation was investigated in 18 sensitized rabbits. Rabbits were separated into three groups: an untreated control group (n = 7), a cimetidine-treated group (n = 6), and an indomethacin-treated group (n = 5). After anesthetization, hyperventilation was performed for 15 min (120 breaths/min, 7 ml/kg tidal volume) with dry air containing 5% CO2. Total lung resistance (RL) and dynamic compliance (Cdyn) were measured before (baseline) and after hyperventilation challenge. After RL and Cdyn had returned to baseline values, the hyperventilation challenge was repeated. In the control group maximal increase in percent RL (max %RL) was 49 +/- 9% after the first challenge, but 16 +/- 4% after the second challenge, indicating refractoriness. A similar tendency was observed in percent Cdyn. In the cimetidine- and indomethacin-treated groups, max %RL were 42 +/- 3% and 60 +/- 15% after the first challenge, and 35 +/- 8% and 60 +/- 7% after the second challenge, respectively, indicating no refractoriness. These results suggest that the H2-receptor and bronchodilating prostanoids play an important role in producing the refractoriness to bronchoconstriction observed in sensitized rabbits after repeated hyperventilation.