Nitric oxide (NO) can alter neuronal excitability by decreasing the current through voltage-sensitive sodium channels. We hypothesized that NO inhibits sodium currents in part by promoting slow inactivation. We performed whole-cell voltage clamp experiments on sensory neurons from the nodose ganglion. The voltage-dependence of inactivation was determined after stepping the neurons to various potentials between -100 and 30 mV for 200 ms (fast inactivation) and 3 min (slow inactivation) prior to depolarization to 10 mV. NO shifted the voltage of half-inactivation for fast and slow inactivation to more hyperpolarized potentials by 7 and 12 mV, respectively. Sodium currents exhibited a more profound closed state and slow inactivation after exposure to NO. These results demonstrate for the fist time that the slow inactivation of sodium currents is subject to modulation. Due to its effects on fast and slow inactivation, NO may cause a prolonged decrease in neuronal excitability.