To investigate the possible role of mast cell histamine release in mediating adenosine 5'-monophosphate (AMP)-induced bronchoconstriction, we have measured the histamine concentration in peripheral venous plasma following inhalation of methacholine, AMP, and allergen in concentrations sufficient to provoke mean maximum decreases in FEV1 of 42.8 +/- 2.2%, 46.5 +/- 3.9%, and 40.9 +/- 4.6%, respectively, in 10 atopic, nonasthmatic subjects. Mean baseline plasma concentrations of histamine were 0.25 +/- 0.02, 0.22 +/- 0.03, and 0.29 +/- 0.03 ng/ml on the methacholine, AMP, and allergen study days, respectively. Plasma histamine did not change following methacholine-induced bronchoconstriction, but increased in 9 out of 10 subjects to a mean maximum value of 0.78 +/- 0.15 ng/ml following inhalation of allergen (p less than 0.005). Following bronchial challenge with AMP, there was a significant elevation in plasma histamine in 9 out of 10 subjects to a mean maximum value of 0.39 +/- 0.03 ng/ml (p less than 0.005). We conclude that AMP-induced bronchoconstriction is associated with the enhanced release of histamine in the airways, probably from airway mast cells. However, the rise in plasma histamine, in being smaller than that occurring with a dose of allergen that provoked a similar degree of bronchoconstriction, suggests that additional mechanisms are operative in mediating the airways response to this nucleotide.