Efficacy of Retigabine in Treating Weakness in a Mouse Model of Hypokalemic Periodic Paralysis

Introduction/Aims Hypokalemic periodic paralysis (HypoKPP) is an ion channelopathy causing episodic skeletal muscle weakness triggered by hypokalemia. Reduced inward rectifier K + (Kir) channel activity contributes to membrane depolarization and paralysis, suggesting that pharmacologic activation of muscle K + channels may restore excitability. The Kv7 channel agonist retigabine previously mitigated low‐K + weakness in HypoKPP models. Here, we tested whether this effect persists under conditions producing sustained, severe weakness. Methods Extensor digitorum longus (EDL) muscles from mice homozygous for the SCN4A R669H mutation were studied by isometric twitch force recording at 34°C, with or without 20 U/L insulin. Weakness was induced by reducing extracellular K + to 1.0 mM. Retigabine (10 μM) was applied to the bath, and twitch force was analyzed by paired or unpaired t tests ( n = 4–7 per group). Results Baseline twitch force in 4.75 mM K + was ~50% lower in HypoKPP than wild‐type muscle ( p = 0.01). Force declined further after 1 h in 4.75 mM K + ( p = 0.016) and was completely lost at 1.0 mM K + with insulin. Retigabine significantly reduced loss of force at both 4.75 and 1.0 mM K + ( p = 0.047 and p = 0.007, respectively). Discussion Kv7 channel activation by retigabine preserved contractile force even during sustained depolarization from severe hypokalemia. These findings extend prior work and support development of K + channel agonists as a therapeutic approach for HypoKPP.