We have examined the effect of the diacylglycerol kinase inhibitor R59022 on histamine release from human lung mast cells and basophils. At 1 microM the drug increased the IgE-dependent release of histamine from human basophils from 19 +/- 5% to 60 +/- 13% (n = 5, p < 0.01). The increase in histamine release was dose dependent with maximum enhancement between 1 and 10 microM. 1 microM R59022 also increased f-met peptide-induced histamine release from 18 +/- 4% to 55 +/- 11% (n = 5, p < 0.05). However, the drug did not significantly increase the release of histamine when the non-physiologic stimulus PMA was used to initiate release. The effect of the drug on anti-IgE-induced release was most marked at lower concentrations of anti-IgE and declined when superoptimal concentrations of anti-IgE were used. As anticipated there was a strong negative correlation (r = 0.764, p < 0.05) between anti-IgE-induced histamine release and the percentage enhancement in the presence of 10 microM R59022. In contrast, to these potent effects on the human basophil the drug failed to affect the anti-IgE-induced release of histamine from human lung mast cells. The data suggest that the R59022 increases the release of histamine induced by anti-IgE in human basophils but not in human lung mast cells. Furthermore, the ability of R59022 to potentiate basophil histamine release is restricted to receptor-mediated stimuli such as anti-IgE and does not extend to non-physiologic stimuli such as the phorbol ester PMA.