Am. J. Respir. Crit. Care Med., Vol 151, No. 2, 02 1995, 321-324.
U46619-induced bronchoconstriction in asthmatic subjects is mediated by acetylcholine release
HG Saroea, MD Inman and PM O'Byrne
Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
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)
