While secretion from nerve endings is strictly controlled by an increase in cytoplasmic free calcium several reports suggest intracellular sodium may serve a regulatory role. Whether sodium acts directly to modulate secretion or indirectly by influencing cytoplasmic calcium dynamics is unknown. This study shows, based on parallel experiments studying [Na+]i, [Ca2+]i and vasopressin secretion, that sodium acts directly to regulate secretion in isolated nerve endings from the rat neurohypophysis. The elevation in secretion that develops is dose‐dependently related to the [Na+]i and can occur in the absence of changes in [Ca2+]i.