Hypoxic augmentation of fast-inactivating and persistent sodium currents in rat caudal hypothalamic neurons

Previous work from this laboratory has indicated that TTX-sensitive sodium channels are involved in the hypoxia-induced inward current response of cau dal hypothalamic neurons. Since this inward current underlies the depolariz ation and increased firing frequency observed in these cells during hypoxia , the present study utilized more detailed biophysical methods to specifica lly determine which sodium currents are responsible for this hypoxic activa tion. Caudal hypothalamic neurons from similar to3-wk-old Sprague-Dawley ra ts were acutely dissociated and patch-clamped in the voltage-clamp mode to obtain recordings from fast-inactivating and persistent (noninactivating) w hole cell sodium currents. Using computer-generated activation and inactiva tion voltage protocols, rapidly inactivating sodium currents were analyzed during normal conditions and during a brief (3-6 min) period of severe hypo xia. In addition, voltage-ramp and extended-voltage-activation protocols we re used to analyze persistent sodium currents during normal conditions and during hypoxia. A polarographic oxygen electrode determined that the level of oxygen in this preparation quickly dropped to 10 Torr within 2 min of in itiation of hypoxia and stabilized at <0.5 Torr within 4 min. During hypoxi a, the peak fast-inactivating sodium current was significantly increased th roughout the entire activation range, and both the activation and inactivat ion values (V-1/2) were negatively shifted. Furthermore both the voltage-ra mp and extended-activation protocols demonstrated a significant increase in the persistent sodium current during hypoxia when compared with normoxia. These results demonstrate that both rapidly inactivating and persistent sod ium currents are significantly enhanced by a brief hypoxic stimulus. Furthe rmore the hypoxic-induced increase in these currents most likely is the pri mary mechanism for the depolarization and increased firing frequency observ ed in caudal hypothalamic neurons during hypoxia. Since these neurons are i mportant in modulating cardiorespiratory activity, the oxygen responsivenes s of these sodium currents may play a significant role in the centrally med iated cardiorespiratory response to hypoxia.