Adenosine added to human basophils before anti-IgE challenge inhibited histamine release, whereas addition after challenge potentiated release. Peak responses for the two effects occurred 15 min before and after challenge respectively. The effects of adenosine on histamine secretion were dose-related over concentration ranges of 1-100 microM for inhibition and 0.01-1 microM for potentiation. The capacity of adenosine to inhibit and potentiate histamine secretion was inversely related to the strength of immunological challenge. The ability of theophylline (50 microM) to inhibit and dipyridamole (1 microM) to enhance slightly adenosine-induced responses, and the differing pharmacological effect of 2',5'-dideoxyadenosine suggested that adenosine's effects on basophil histamine secretion were mediated by stimulation of cell surface adenosine receptors. The order of potency of adenosine and its analogues L- and D- N6-phenylisopropyladenosine (PIA) and 5'-N-ethylcarboxamideadenosine (NECA) in inhibiting and potentiating IgE-dependent histamine release from basophils indicated that both responses were mediated by stimulation of the adenosine A2-receptor subtype. The capacity of adenosine to cause a transient increase of cyclic AMP levels in 40-70% basophil-enriched leucocytes confirmed the association between stimulation of A2-receptors and activation of adenylate cyclase.