U46619-induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine release

Thromboxane A2 (TxA2) has been implicated in the pathogenesis of airway hyperresponsiveness. U46619 is a chemical that mimics the effects of TxA2. Both TxA2 and U46619 have been demonstrated to act presynaptically to enhance the release of acetylcholine from cholinergic nerves in canine airway smooth muscle. The purpose of this study was to determine whether the bronchoconstriction caused by inhaled U46619 in asthmatic subjects is caused by acetylcholine release. Airway responsiveness to inhaled methacholine and U46619 was measured in eight subjects with mild stable asthma and expressed as the provocation concentration causing a 20% fall in FEV1 (PC20). Subjects were studied on 4 d, each separated by 3 days. On each study day, subjects inhaled a cholinergic antagonist ipratropium bromide (80 micrograms), or placebo, and 1 h later, increasing doubling doses of methacholine or U46619 were inhaled, and a PC20 value was obtained. The mean methacholine PC20 on the placebo day was 1.42 mg/ml (%SEM, 1.47) and after treatment with ipratropium bromide this increased to 127.33 mg/ml (%SEM, 1.29) (p = 0.0001), a mean 89.4-fold (%SEM, 1.19) increase. The mean U46619 PC20 on the placebo day was 2.09 micrograms/ml (%SEM, 1.56) and after treatment with ipratropium bromide this increased to 47.54 micrograms/ml (%SEM, 1.43) (p = 0.0001), a mean 22.8-fold (%SEM, 1.36) increase. The ability of ipratropium bromide to attenuate responsiveness to the noncholinergic mediator histamine was also investigated in six subjects. The mean increase in histamine PC20 was a 3.09-fold (%SEM, 1.17) increase, significantly less than the increase seen for both methacholine and U46619 (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)