The purine nucleosides adenosine and 2',5'-dideoxyadenosine (2',5'ddAdo) enhance and inhibit respectively the anti-IgE-induced secretion of histamine and transient rise in cellular levels of cyclic AMP in rat mast cells. These findings have provided evidence for a role for cyclic AMP in the activation of mast cell secretion. It has been generally accepted that the nucleosides mediate their effects on mast cells by altering adenylate cyclase activity. We have investigated the effect of various purine and ribose modified analogues of adenosine on secretion of histamine from rat mast cells induced by ionophore A23187 for which there is no associated elevation in cyclic AMP and no evidence for the activation of adenylate cyclase in its mechanism of action. Adenosine and N6, phenylisopropyladenosine (0.01-1000 microM) (activators of adenylate cyclase in many tissues) enhanced the secretion of histamine induced by ionophore A23187 and anti-IgE. Two inhibitors of adenylate cyclase had differential effects on secretion. 2',5'ddAdo (100-1000 microM) inhibited both A23187-and anti-IgE-mediated secretion; whilst 9-beta-D-arabinofuranosyladenine had no effect on secretion. These results suggest that the ability of these nucleosides to modulate histamine secretion is unrelated to their effects on adenylate cyclase.