Dl-palmitoylcarnitine in combination with low concentrations (0.2 microM) of the ionophore A23187 induced a pronounced non-cytotoxic histamine release, with maximal response at 10 microM palmitoylcarnitine and a lower response at 20 microM. The concentration-response curve was shifted to the right when the mast cells were preincubated with palmitoylcarnitine before exposure to the ionophore. Palmitoylcarnitine alone was without effect at concentrations below 20 microM but cytotoxic at higher concentrations. The response to the combination of palmitoylcarnitine and the ionophore was highly sensitive to changes in the ionophore concentration. The results indicate that conditions allowing physicochemical interactions between the two drugs led to greatest potency and effectiveness of palmitoylcarnitine. Preincubation with the phorbol ester TPA potentiated the response. The release induced by the combination of palmitoylcarnitine and the ionophore was completely inhibited by low concentrations of the flavonoid phloretin (IC50 of 0.5 - 2 microM) whereas the protein kinase inhibitor H-7 enhanced the response. The synergistic response to palmitoylcarnitine and the ionophore and its affection by phloretin and H-7 resembles previous findings with TPA and the ionophore. Although not conclusive the results indicate that palmitoylcarnitine can stimulate mast cells by activation of protein kinase C.