The present study was undertaken to determine whether nitric oxide (NO) alters voltage-dependent changes in intracellular calcium levels ([Ca2+]i) using PC12 cells as a neuronal model. The addition to PC12 cells of sodium nitroprusside (SNP), which spontaneously releases NO in aqueous solution, significantly inhibited the KCl-stimulated increase in [Ca2+]i. The inhibitory action of SNP was concentration-dependent and was mimicked by hydroxylamine which also generates NO. Both L-type (nifedipine sensitive) and N-type (omega-conotoxin sensitive) voltage-dependent Ca2+ channels are present in PC12 cells and may be affected by NO-generating agents. In contrast, SNP did not alter [Ca2+]i in response to purinergic receptor stimulation. Preincubation of PC12 cells with 8-bromo-cyclic GMP also inhibited the KCl-stimulated increase in [Ca2+]i. In addition, inclusion of the guanylyl cyclase inhibitor, LY83583, blocked the inhibitory action of SNP on the voltage-sensitive changes in [Ca2+]i. The results suggest that NO selectively inhibits voltage-dependent calcium influx in neuronal cells through a cyclic GMP-dependent mechanism.