Indomethacin and methacholine tolerance in normal subjects. Role of prostaglandin synthesis in the attenuation of methacholine's effect during repeated inhalation challenges.

Within hours, tolerance occurs to repeated methacholine challenge in normal subjects, and this study examines whether prostaglandin synthesis produces this phenomenon. On two separate study days, ten nonasthmatic non-smoking subjects with measurable baseline responsiveness to methacholine performed five sequential methacholine challenge tests over 6 h. Pretreatment before each day consisted of either placebo tablets or 50-mg tablets of indomethacin given three times daily for 48 h prior to testing. Medications were administered in a single-blind crossover fashion, with study days assigned in random order and separated by at least 1 wk. Methacholine challenge tests were summarized by the PD20FEV1 (the provocative dose in cumulative breath units [cbu] required to produce a 20 percent fall in FEV1). Indomethacin pretreatment had no effect on baseline spirometry between the two study days; however, the baseline geometric mean PD20FEV1 fell from 145 +/- 2 cbu (+/- percent SD) after placebo pretreatment to 65 +/- 1 cbu (+/- percent SD) on the indomethacin day (p = 0.046). This effect of indomethacin on baseline airway responsiveness persisted when an additional ten subjects were studied to further investigate this finding. Significant tolerance to repeated methacholine challenges occurred on both study days, with geometric mean PD20FEV1 rising approximately 16-fold (p less than 0.0001) regardless of pretreatment received. This study demonstrates that the attenuation of methacholine's effect with repeated testing is not due solely to prostaglandin synthesis and must involve, in part, other mechanisms, such as changes in methacholine deposition, agonist-receptor interactions, or postreceptor responses. In addition, prostaglandin inhibitors may increase baseline methacholine responsiveness in healthy nonasthmatic subjects.