Adenosine-induced bronchoconstriction in human asthmatics: Effects of pretreatment with indomethacin or atropine sulfate

Abstract

The present investigation was designed to evaluate the effects of pre-treatment with the cholinergic muscarinic receptor antagonist, atropine sulfate, or with the cyclooxygenase inhibitor, indomethacin, on adenosine-induced bronchoconstriction in human asthmatics. Eight male subjects with a FEV 1 of > 70% of the predicted normal value underwent bronchial provocation challenges with adenosine and with the cholinergic agonist, methacholine, in a double-blind, randomized, cross-over fashion. The log 10 of the agonist dose provoking a 20% decrease in FEV 1 (log PD 20FEV 1) was used to assess airways responsiveness. Challenges were performed in the untreated state and 30 min after inhalation of atropine sulfate (0.05 mg/kg). Pre-challenge FEV 1 values after atropine inhalation were higher than in the untreated state (p < 0.01). Without atropine, the log PD 20FEV 1 values for adenosine were higher than those for methacholine (p < 0.01). Atropine prevented a decrease in the FEV 1 of 20% or more in seven of the eight subjects following inhalation of methacholine up to a concentration of 25 mg/ml, but did not significantly change the log PD 20FEV 1 for adenosine. The effects of a 75 mg oral dose of indomethacin or placebo, administered in a double-blind, randomized, cross-over fashion two hours before adenosine or methacholine challenge, were assessed in 12 asthmatics. In four subjects (two after placebo and two after indomethacin pretreatment), aerosols of the highest adenosine concentration (10 mg/ml) failed to decrease the FEV 1 by 20% or more. In the remaining eight subjects, log PD 20FEV 1 values for adenosine or methacholine after indomethacin were not significantly different from those after placebo. These data corroborate observations with the quaternary atropine cogener, ipratropium bromide, that adenosine-induced bronchoconstriction is not mediated via efferent vagal pathways. The data further suggest that adenosine's effects on bronchial smooth muscle tone in human asthmatics are not mediated or modulated by cyclooxygenase products of arachidonic acid metabolism.