Indomethacin blocks airway tolerance to repetitive exercise but not to eucapnic hyperpnea in asthmatic subjects

We have examined the effects of indomethacin (I) on tolerance to the bronchomotor effects of repetitive challenge with exercise (EX) and eucapnic hyperpnea (EH) in 7 asthmatic subjects. Each subject was studied on 4 separate days. EH was performed for 4 min at a minute ventilation found previously to increase specific airway resistance (SRaw) by 8 units (cmH₂O/L/s). All exercise challenges were performed on a cycle ergometer for 5 min at a constant work load. Subjects breathed room temperature, dry air for both stimuli. SRaw was serially measured before and after each stimulus. Tolerance was examined by giving up to 3 repetitions of EH or EX, allowing a return of SRaw to within 1 unit of baseline between repetitions. Placebo (P) or I (25 mg four times a day for 7 doses) was administered in a single-blind manner. The timing between stimulus repetitions on the P day was matched to that of the I day. After P, the initial rise in SRaw was similar for both EX and EH, with a significant and progressive decrease in this rise after each stimulus repetition (p = 0.032 for EX, P = 0.006 for EH). After I, tolerance was still demonstrated to EH (p = 0.002, but not to EX (p = 0.231). This finding indicates that EH and EX are not identical stimuli, since there is an I-sensitive mechanism (possibly a bronchodilating prostaglandin) associated with the development of tolerance to EX but not to EH. Our data also suggest a possible additional bronchoconstricting mechanism associated with EX and not with EH.