Adenosine by inhalation causes bronchoconstriction in asthmatic but not in normal subjects by an undefined mechanism. This study investigated the roles of cholinergic reflex stimulation and decreased beta 2-adrenoceptor responsiveness to explain adenosine's bronchoconstrictor action. The protection afforded by the inhaled muscarinic cholinergic antagonist, ipratropium bromide (IB) 1 mg, from bronchoconstriction induced by inhaled adenosine was compared with that of methacholine in 8 allergic asthmatic subjects. After saline placebo, the geometric mean concentrations of adenosine required to produce a 20% fall in FEV1 (PCf20) was 2.20 mg/ml and a 35% fall in SGaw (PCs35) was 1.97 mg/ml, which compared to 0.13 and 0.11 mg/ml, respectively, for methacholine. The IB increased FEV1 by 11 to 15% and SGaw by 69 to 73% and provided a large degree of protection against methacholine, with a geometric mean concentration ratio (CR) of 196 when airway caliber was measured as SGaw (p less than 0.001). In contrast, IB provided little protection against adenosine-induced bronchoconstriction (CR 1.3 for SGaw and 1.51 for FEV1). Beta 2-adrenoceptor responsiveness of the airways after inhaled adenosine and histamine was further studied in 12 asthmatic subjects by observing the antibronchoconstrictor effect of inhaled isoproterenol. After equivalent degrees of bronchoconstriction, 35 to 36% fall in FEV1 and 60 to 62% fall in SGaw cumulative doses of inhaled isoproterenol produced almost identical maximal increases in FEV1 and SGaw after adenosine as achieved after histamine.(ABSTRACT TRUNCATED AT 250 WORDS)