Inhaled adenosine causes bronchoconstriction in asthmatic patients. Antagonism of the bronchoconstrictor effect of endogenous adenosine has been processed as a possible mechanism of action of theophylline in asthma. To directly investigate this the airway responses to inhaled adenosine and histamine, with and without the prior administration of inhaled theophylline, were compared in 8 allergic asthmatic [human] subjects. Airway response was measured as forced expiratory volume in 1 s (FEV1) and as specific airway conductance (SGaw). Inhaled adenosine was less potent than histamine in producing bronchoconstriction, with geometric mean concentrations required to produce a 20% fall of FEV1 (PCf20) and a 40% fall of SGaw (PCs40) being 0.27 and 0.25 mg/ml for adenosine and 0.10 and 0.09 mg/ml for histamine. In a total nebulized dose of 37.5 mg, inhaled theophylline was a weak bronchodilator that caused maximal increases in FEV1 of 2 .+-. 2% (mean .+-. SE, P < 0.05) and in SGaw of 8 .+-. 4% (P > 0.05). Theophylline significantly inhibited adenosine-induced bronchoconstriction, increasing the PCf20 and PCs40 values for adenosine to 1.66 (P < 0.001) and 2.34 (P < 0.005) mg/ml, respectively. Inhibition of histamine-induced bronchoconstriction was less marked, with PCf20 and PCs40 values of 0.19 (P > 0.05) and 0.21 (P < 0.05) mg/ml. Adenosine is a bronchoconstrictor in asthma whose effects are preferentially antagonized by concentrations of theophylline that cause little change in baseline airway caliber. Adenosine antagonism should be considered as a possible factor contributing to the pharmacologic efficacy of methyl xanthines in asthma.