Mediobasal hypothalamic (MBH) slices of male adult rats were superfused at 37 °C with oxygenated Hepes-buffer Locke medium. Bacitracin (2 × 10<sup>–5</sup>MJ was added to prevent enzymatic degradation of LHRH and SRIF. 6 min pulse of K<sup>+</sup> (56 m M), veratridine (15 µ M) or the ionophore A 23187 (10<sup>–5</sup> M), markedly stimulated the release of both neuropeptides. Trifluoperazine, a calmodulin inhibitor, decreased the K<sup>+</sup>-evoked LHRH and SRIF release in a dose-dependent manner; it was also effective in inhibiting the veratridine-induced neuropeptides release. Phenytoin, a calmodulin-dependent kinase inhibitor, also decreased in a dose-dependent manner the K<sup>+</sup>-induced LHRH and SRIF release; the basal release of both neuropeptides remained unaffected by either treatment. The ionophore-stimulated release of both neuropeptides was significantly inhibited as well. These data demonstrate that a Ca<sup>++</sup>-calmodulin kinase system may be involved in the mechanism of depolarization-induced LHRH and SRIF release from hypothalamic nerve terminals.