Retigabine Suppresses Loss of Force in a Mouse Model of Hypokalemic Periodic Paralysis

Objective The goal of this experimental study was to test the hypothesis that the potassium channel opener retigabine can prevent the episodic loss of force in hypokalemic periodic paralysis (HypoPP). Methods A knock-in mutant mouse model of HypoPP ( Scn4a p.R669H) was used to determine whether pretreatment with retigabine suppressed the loss of force, or post-treatment hastened recovery of force for a low-K + challenge in an ex vivo contraction assay. Results Retigabine completely prevents the loss of force induced by a 2 mM K + challenge (protection) in our mouse model of HypoPP, with a 50% inhibitory concentration (IC 50 ) of 0.8 µM. In comparison, the effective concentration for the K ATP channel opener pinacidil was ten-fold higher. Application of retigabine also reversed the loss of force (rescue) for HypoPP muscle maintained in 2 mM K + . Interpretation Retigabine, a selective agonist of the K V 7 family of potassium channels, is effective for the prevention of low-K + induced attacks of weakness and to enhance recovery from an on-going loss of force in a mouse model of HypoPP. Substantial protection from the loss of force occurred in the low micromolar range, well within the therapeutic window for retigabine.