Hypertonic stimuli delivered into the supraoptic nucleus provoke neuropeptide release from the somata of magnocellular neurosecretory cells (MNCs) in the presence of tetrodotoxin, suggesting that such stimuli can increase intracellular calcium concentration ([Ca2+]i) in the absence of action potentials. We therefore examined whether the stretch-inhibited cation (SIC) channels of MNCs can mediate calcium influx. Whole-cell recordings were made in MNCs isolated from the supraoptic nuclei of adult rats. Measurements of reversal potentials in different solutions revealed that the current induced by a suction-evoked decrease in cell volume (ISIC) displays a selectivity sequence for monovalent cations of K+ > Cs+ > Na+ > NMDG+. The permeability of SIC channels to Ca2+, relative to Na+, was ∼ 5. In the presence of physiological concentrations of external Na+ and K+, the amplitude of inward ISIC was reduced dose-dependently by external Ca2+ with an IC50 of 4.9 mm. This was not due to reduced suction-evoked volume changes or to an accumulation of [Ca2+]i. Confocal imaging of cytoplasmic Calcium Green-1 fluorescence revealed that activation of ISIC significantly increases [Ca2+]i in physiological solutions. This effect is absent in Ca2+-free solution, or when Gd3+ (300 µm) is added to Ca2+-containing solution. Part of this effect is inhibited in the presence of dantrolene (10 µm) and heparin (4 mg/mL), suggesting that release from intracellular Ca2+ stores participates in suction-evoked Ca2+ signalling. These observations indicate that SIC channels are highly permeable to Ca2+, mediate significant Ca2+ entry and release of Ca2+ from internal stores under conditions when the volume of MNCs is decreased.