The ionic current underlying the upstroke of axonal action potentials is carried by rapidly activating, voltage-dependent Na+ channels. Termination of the action potential is mediated in part by the rapid inactivation ofthese Na+ channels. We previously demonstrated that an influx of Na+ plays a critical role in the cascade leading to irreversible anoxic inwjury in central nervous system white matter. We speculated that a noninactivating Na+ conductance mediates this pathological Na+ influx and persists at depolarized membrane potentials as seen in anoxic axons. In the present study we measured the resting compound membrane potential of rat optic nerves using a modified "grease-gap" technique. Application of tetrodotoxin (2 gzM) to resting nerves ([K+]J = 3 mM) or to nerves depolarized by 15 or 40 mM K+ resulted in hyperpolarizing shifts of membrane potential. We interpret these shifts as evidence for a persistent, noninactivating Na+ conductance. This conductance is present at rest and persists in nerves depolarized sufficiently to abolish classical transient Na+ currents. PK/PNa ratios were estimated at 35.5, 23.2, and 88 in 3 mM, 15 mM, and 40 mM K+, respectively. We suggest that this noninactivating Na+ conductance may provide an inward pathway for Na+ ions, necessary for the operation of Na+,K+-ATPase. Under pathological conditions, such as anoxia, this conductance is the likely route of Na+ influx, which causes damagng Ca2+ entry through reverse operation of the Na+ Cal+ exchanger. The presence of this conductance in white matter axons may provide a therapeutic opportunity for diseases such as stroke and spinal cord injury.Voltage-dependent Na+ channels are responsible for the rapid membrane depolarization underlying axonal action potentials. The classical description of the kinetics of these channels requires rapid activation to initiate the upstroke of the action potential. The action potential is terminated in part by a quick and complete inactivation of Na+ conductance at depolarized potentials (1). In addition to the rapidly inactivating Na+ channel usually associated with action potential initiation and propagation, a different type of voltage-gated Na+ conductance has been described (2). Like the classical Na+ channel, this conductance rapidly activates with depolarization but inactivates either very slowly or incompletely even with prolonged depolarization (3-6).In previous studies on the pathophysiology of white matter anoxic injury, we speculated that a noninactivating Na+ conductance might play a critical role in the ionic events that lead to damaging increases in intracellular Ca2+ (7). Our experiments revealed that reverse Na+-Ca2+ exchange mediates Ca2+ overload in anoxic white matter and demonstrated that reverse exchange depends on an increase in intracellular [Na+] caused by a tetrodotoxin (TTX)-sensitive Na+ influx across the axon membrane. This influx appears toThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be here...