Efficacy of sodium channel blockers in treating myotonia is independent of action potential sodium current block

The prevailing view holds that the therapeutic benefit of sodium channel blockers arises from use-dependent inhibition of the transient sodium current (NaT) that is responsible for action potentials. This assumption underlies decades of drug development but has never been directly tested. Our goal was to test this assumption to guide the development of more effective sodium channel blockers. We used a mouse model of myotonia congenita, an ion channelopathy of skeletal muscle, as a system to study mechanism and efficacy of both use-dependent and closed sodium channel blockers. Intracellular current-clamp recordings were used to assess excitability during trains of stimuli. The contributions of NaT and a small, non-inactivating current (Na persistent or NaP) were directly measured with voltage-clamp recordings. At their effective concentrations none of the sodium channel blockers reduced action potential rate of rise or voltage clamp measures of NaT. In contrast at effective concentrations, all sodium channel blockers studied reduced NaP. A computational model was constructed to test the relative effects of NaT and NaP inhibition on excitability. The model confirmed that NaT block alone could not eliminate myotonia without causing hypoexcitability, whereas partial NaP block was sufficient to abolish pathological discharges while preserving normal firing. These findings redefine the therapeutic mechanism of sodium channel blockade: efficacy does not depend on blocking NaT but correlates with the inhibition of NaP. This shift in perspective reframes strategies for sodium channel drug development and suggests a novel approach to treating myotonia, neuropathic pain, cardiac arrythmia and epilepsy. KEY POINTS: At effective doses that treat hyperexcitability, Na channel blockers have little effect on the sodium current responsible for action potentials. Electrophysiologic recordings and computer simulation suggest that block of a small, persistent, sodium current (NaP) is the mechanism underlying efficacy in treating hyperexcitability. These findings suggest that screens for novel sodium channel blockers focus on block of NaP.