The phorbol ester 12-0-tetradecanoylphorbol-13-acetate (TPA) induces a slow secretion of histamine from rat peritoneal mast cells. This secretion is dose-dependent from 0.3 to 10 ng/ml. Higher doses are less efficient. The absence of magnesium and/or potassium increases mast cell exocytosis induced by TPA. In the absence of both potassium and magnesium, extracellular calcium concentrations above 3 X 10(-5)M inhibit the effect of TPA. The sensitivity of mast cells to other inducers of histamine release is modified by pretreatment with TPA. The ionophore A23187-induced secretion is potentiated or inhibited according to the dose of TPA and the concentration of extracellular calcium. The absence of potassium prevents the potentiating effect of TPA. The secretory effect of compound 48/80 is decreased by pretreatment of mast cells with TPA. This effect is more potent in the absence of potassium. These results suggest that the activation of protein kinase C acts as a bidirectional regulator of mast cell exocytosis and is modulated by transmembrane gradients of monovalent and divalent ions. Its inhibitory effects might be favoured by the highest levels of cytosolic calcium and could be related to the inhibition of a guanine nucleotide regulatory protein involved in the transduction of the receptor signal to phosphatidylinositides turnover.