Effect of adenosine, adenosine analogs and methylxanthines was studied on histamine release induced by antigen, compound 48/80, α-chymotrypsin, substance P and neurotensin from rat peritoneal mast cells.Adenosine inhibited anaphylactic histamine release at low concentrations but enhanced it at higher concentrations. N(6)-methyladenosine, an adenosine R-site analog, had a similar dual effect on anaphylactic histamine release. However, 9-β-D-arabinofuranosyladenine and 2'-deoxyadenosine, adenosine P-site analogs, had neither inhibitory nor enhancing effect. Adenosine inhibited histamine release induced by compound 48/80 and α-chymotrypsin but not the release induced by substance P and neurotensin. Not only adenosine R-and P-site analogs, but also a large variety of purine and pyrimidine derivatives inhibited compound 48/80-induced histamine release. Theophylline inhibited compound 48/80-induced histamine release. However, 3-isobutyl-l-methylxanthine, caffeine and theobromine were ineffective.These results suggest that adenosine inhibits anaphylactic histamine release by stimulating adenosine R(i) receptors but enhances the release by stimulating R(a) receptors. It is also suggested that the inhibition by adenosine of compound 48/80-induced histamine release is not caused by the stimulation of specific adenosine receptors. By either the antagonism at adenosine receptors or the inhibition of phosphodiesterase it seems to be difficult to explain the inhibition by theophylline of compound 48/80-induced histamine release.