Hypoxia and persistent sodium current

Abstract

During prolonged depolarization of excitable cells, some voltage-activated, tetrodotoxin-sensitive sodium channels are resistant to inactivation and can continue to open for long periods of time, generating a "persistent" sodium current (INaP). The amplitude of INaP is small [generally less than 1% of the peak amplitude of the transient sodium current (INaT)], activates at potentials close to the resting membrane potential, and is more sensitive to Na channel blocking drugs than INaT. It is thought that persistent Na channels are generated by a change in gating of transient Na channels, possibly because of a change in phosphorylation or protein structure, e.g. loss of the inactivation gate. Drugs that block Na channels can prevent the increase in [Ca2+]i in cardiac cells during hypoxia. Hypoxia increases the amplitude of INaP. Paradoxically, NO causes a similar increase in INaP and the effects of both can be inhibited by reducing agents such as dithiothreitol and reduced glutathione. It is proposed that an increased inflow of Na+ during hypoxia increases [Na+]i, which in turn reverses the Na/Ca exchanger so that [Ca2+]i rises. An increase in INaP and [Ca2+]i could cause arrhythmias and irreversible cell damage.