Adenosine-5'-monophosphate (AMP) is a bronchoconstrictor agonist in subjects with atopic and nonatopic asthma. In this study we have investigated the effect of repeated airway challenge with AMP in 10 atopic, subjects without asthma. At the first visit, subjects had repeated inhalation challenges with increasing doubling concentrations of AMP, and the provocation concentration required to reduce FEV1 by 20% of baseline was determined (PC20 AMP). When the FEV1 had returned to within 5% of the baseline, the AMP challenge test was repeated on a further one or two occasions. When the maximum concentration of AMP (400 mg/ml) failed to produce a PC20, a bronchial provocation test with histamine was performed and the PC20 was determined. On the second visit, the effect of three consecutive inhalation challenge tests with histamine on the airway response to this agonist was determined. On the third visit, the duration of induced refractoriness to AMP was assessed. With the first AMP challenge, all subjects demonstrated bronchoconstriction with a geometric mean (GM) PC20 of 332 mg/ml. With a second AMP challenge, five of the 10 subjects became refractory and failed to achieve a PC20. In the remaining five subjects, the GM PC20 increased from 110 to 583 mg/ml. With a third AMP challenge, these subjects also failed to achieve a PC20. The initial GM PC20 histamine for the group was 22.9 mg/ml, which did not change significantly with two further histamine challenges or when the airways were refractory to AMP, suggesting that loss of AMP effect was not related to loss of contractility of airway smooth muscle or down regulation of H1-histamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)