1. The release of arginine vasopressin (AVP) from a perifused preparation of peptidergic nerve terminals isolated from rat neurohypophyses was studied during manipulations of the external sodium and calcium concentrations. Intracellular concentrations of these two ions were manipulated by use of ouabain and a calcium ionophore, respectively. 2. Removal of extracellular Na+ caused, in a concentration-dependent manner, a significant decrease of secretory activity. Conversely, graded addition of Na+ to a Na(+)-free perifusion medium increased secretion. Half-maximal activation of secretory activity was attained at ca 75 mM [Na+]o. 3. Manipulations of extracellular Ca2+ did not affect the level of hormonal secretion in the absence of extracellular Na+. However, when Na+ was present in the perifusion medium, removal of extracellular Ca2+ induced an increase of secretory activity. 4. The effects of manipulations of [Na+]o were not dependent on the presence of Ca2+ in the perifusion medium nor on the nature of the Na+ replacement used (i.e. choline or mannitol). 5. Ouabain (0.1 mM) increased the basal secretory activity and potentiated the secretory response to removal of Ca2+ from the perifusion medium. 6. The Ca2+ ionophore A23187 stimulated, in a concentration-dependent fashion, the secretory activity of the peptidergic nerve terminals and this stimulation was strictly dependent on the presence of Ca2+ in the perifusion medium. 7. These results show that basal secretion is directly dependent on [Na]o and indicate that intracellular Na+ is an important factor in the control of secretory mechanisms. Evidence is presented in regard to a possible antagonistic effect of extracellular Ca2+ and Na+ on secretion.