U46619-INDUCED BRONCHOCONSTRICTION IN ASTHMATIC SUBJECTS IS MEDIATED BY ACETYLCHOLINE-RELEASE

Thromboxane A(2) (TxA(2)) has been implicated in the pathogenesis of a irway hyperresponsiveness. U46619 is a chemical that mimics the effect s of TxA(2). Both TxA(2) and U46619 have been demonstrated to act pres ynaptically to enhance the release of acetylcholine from cholinergic n erves 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 respons iveness to inhaled methacholine and U46619 was measured in eight subje cts with mild stable asthma and expressed as the provocation concentra tion causing a 20% fall in FEV(1) (PC20). Subjects were studied on 4 d , each separated by 3 days. On each study day, subjects inhaled a chol inergic antagonist ipratropium bromide (80 mu g), or placebo, and 1 h later, increasing doubling doses of methacholine or U46619 were inhale d, and a PC20 value was obtained. The mean methacholine PC20 on the pl acebo day was 1.42 mg/ml (%SEM, 1.47) and after treatment with ipratro pium 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 pl acebo day was 2.09 mu g/ml (%SEM, 1.56) and after treatment with iprat ropium bromide this increased to 47.54 mu g/ml (%SEM, 1.43) (p = 0.000 1), a mean 22.8-fold (%SEM, 1.36) increase. The ability of ipratropium bromide to attenuate responsiveness to the noncholinergic mediator hi stamine was also investigated in six subjects. The mean increase in hi stamine PC20 was a 3.09-ford (%SEM, 1.17) increase, significantly less than the increase seen for both methacholine and U46619 (p < 0.001). These results demonstrate that the bronchoconstrictor effect of inhale d U46619 is markedly attenuated by a cholinergic antagonist, and they support the hypothesis that thromboxane-induced bronchoconstriction re sults in part from acetylcholine release from cholinergic nerves in as thmatic airways.