Mast cells release many biologically active molecules upon stimulation by a variety of molecules such as immunoglobulin E (IgE) and specific antigen, anaphylatoxins, as well as a number of cationic compounds which include drugs, kinins and neuropeptides. The effect of the naturally occurring polyamine spermine was studied because, even though it is polycationic, it has been implicated in the modulation of secretory processes in a variety of cells. In particular, it was previously shown that oxidation products of spermine inhibit mast cell secretion. High concentrations of spermine (5 x 10(-3) M) added at 37 degrees C induced mast cell secretion that had similar characteristics with that triggered by compound 48/80 (48/80). However, spermine inhibited mast cell secretion in a dose-dependent manner as long as it was added at 4-10 degrees C for at least 10 min in the absence of Ca++ before warming the cells to 37 degrees C and triggering them with 48/80. These findings were true both for purified rat peritoneal mast cells and for rat skin mast cells in situ. Addition of calcium after the cells had been warmed to 37 degrees C could not reverse this inhibition. The inhibition seen when spermine was added at 4 degrees C was, however, overcome if phorbol myristate acetate (PMA) or NaF, which activate PKC and G proteins respectively, were added to mast cells at 37 degrees C together with Ca++. These results indicate that polyamines could be important modulators of the activation state of mast cells and might help further define the biochemical events involved in mast cell secretion.