The influence of refractoriness to adenosine 5'-monophosphate on allergen-provoked bronchoconstriction in asthma

Repeated bronchoprovocation with adenosine 5'-monophosphate (AMP) in atopic, nonasthmatic subjects produces a state of refractoriness to the nucleotide that may be due either to depletion of preformed mediators from airway mast cells or down-regulation of purinoceptors on the surface of these cells. To investigate this further, we compared the effect on immediate allergen-provoked bronchoconstriction of preceding repeated challenges with histamine and AMP in eight atopic, mildly asthmatic subjects. In three successive AMP concentration-response studies, the geometric mean PC20 AMP increased from 275.3 to 1154.3 (p less than 0.01) and 1976.7 (p less than 0.01) mg/ml, respectively, whereas no significant similar increase in PC20 occurred with repeated histamine challenges. Refractoriness to AMP was not associated with any significant decrease in airways responsiveness to histamine. When compared with the response after repeated provocation with inhaled histamine, repeated exposure of the airways to AMP potentiated, rather than inhibited, immediate allergen-induced bronchoconstriction by a mean 57 +/- 22.6% (p less than 0.05) when the data were expressed as the area under the FEV1-time response curve. The ability of airways that have been rendered less responsive to inhaled AMP to exhibit an increased response to allergen suggests that tachyphylaxis to AMP is unlikely to be caused by depletion of preformed mast cell-derived mediators such as histamine.