HCO - 3 modulation of histamine release and its relationship with the Ca 2 + signal were studied in serosal rat mast cells. Histamine release was induced by Ca 2 + mobilizing stimuli, namely compound 48/80, thapsigargin, Ca 2 + chelators, ionophore A23187, and PMA and ionophore A23187 in a HCO - 3 -buffered medium or a HCO - 3 -free medium. The presence of HCO - 3 reduced histamine release by 48/80, Ca 2 + chelators, A23187, and PMA/A23187, but increased histamine release induced by thapsigargin. Histamine release by PMA was significantly higher in a HCO - 3 -free medium than in a HCO - 3 -free medium, as it was the PMA potentiation of histamine release by A23187. [Ca 2 + ] i changes induced by these drugs were measured in fura-2-loaded mast cells. In thapsigargin and EGTA or BAPTA preincubated mast cells [Ca 2 + ] i increase was higher in a HCO - 3 -buffered medium than in a HCO - 3 -free medium in the presence of Ca 2 + . On the contrary, in compound 48/80 and PMA/A23187 activated mast cells the [Ca 2 + ] i increase is the same both in the presence and in the absence of HCO - 3 . The effect of HCO - 3 on histamine release in serosal rat mast cells depends on the stimulus, but it is not related to the presence of Cl - . In thapsigargin-stimulated mast cells the effect of HCO - 3 on histamine release may be related to the Ca 2 + signal, but in compound 48/80, EGTA, and PMA/A23187-activated mast cells there is no relationship between intracellular Ca 2 + and the inhibitory effect of HCO - 3 on histamine release. Additionally, the PKC pathway is implicated in the inhibitory effect of HCO - 3 on histamine release, the higher the chelation of calcium rendering the higher the enhancement of the response after adding calcium in the absence of HCO - 3 .