Magnocellular neurosecretory cells (MNCs), of the paraventricular and supraoptic nuclei of the hypothalamus, secrete the hormones vasopressin and oxytocin. As a result, they have an essential role in fundamental physiological responses including regulation of blood volume and fluid homeostasis. C-type natriuretic peptide (CNP) is present at high levels in the hypothalamus. Although CNP is known to decrease hormone secretion from MNCs no studies have examined the role of the natriuretic peptide C receptor (NPR-C) in these neurons. In this study, whole-cell recordings from acutely isolated MNCs, and MNCs in a coronal slice preparation, show that CNP (2 x 10^-8 M) and the selective NPR-C agonist, cANF (2 x 10^-8 M), significantly inhibit L-type Ca²⁺ current (I_Ca(L)) by ~50%. This effect on I_Ca(L) is mimicked by dialyzing a G_i-activator peptide (10^-7 M) into these cells, implicating a role for the inhibitory G protein, G_i. These NPR-C mediated effects were specific to I_Ca(L) as T-type Ca²⁺ channels were unaffected by CNP. Current clamp experiments revealed the ability of CNP, acting via the NPR-C receptor, to decrease (~25 %) the number of action potentials elicited during a 500 ms depolarizing stimulus. Analysis of action potential duration revealed that CNP and cANF significantly decreased APD₅₀ in MNCs. In summary, our findings demonstrate that CNP has a potent and selective inhibitory effect on I_Ca(L) and on excitability in MNCs that is mediated by the NPR-C receptor. These data represent the first electrophysiological evidence of a functional role for the NPR-C receptor in the mammalian hypothalamus.