Retigabine completely prevented the loss of force induced by a 2 mM K+ challenge in mouse models of HypoPP, with IC50s of 0.8 ± 0.13 μM and 2.2 ± 0.42 μM.
Does retigabine prevent or reverse the loss of force induced by a low-K+ challenge in mouse models of hypokalaemic periodic paralysis?
Retigabine effectively prevents and reverses low-potassium induced loss of force in mouse models of hypokalaemic periodic paralysis.
Recurrent episodes of weakness in periodic paralysis are caused by intermittent loss of muscle fibre excitability, as a consequence of sustained depolarization of the resting potential. Repolarization is favoured by increasing the fibre permeability to potassium. Based on this principle, we tested the efficacy of retigabine, a potassium channel opener, to suppress the loss of force induced by a low-K+ challenge in hypokalaemic periodic paralysis (HypoPP). Retigabine can prevent the episodic loss of force in HypoPP. Knock-in mutant mouse models of HypoPP (Cacna1s p.R528H and Scn4a p.R669H) were used to determine whether pre-treatment with retigabine prevented the loss of force, or post-treatment hastened recovery of force for a low-K+ challenge in an ex vivo contraction assay. Retigabine completely prevents the loss of force induced by a 2 mM K+ challenge (protection) in our mouse models of HypoPP, with 50% inhibitory concentrations of 0.8 ± 0.13 μM and 2.2 ± 0.42 μM for NaV1.4-R669H and CaV1.1-R528H, respectively. In comparison, the effective concentration for the KATP channel opener pinacidil was 10-fold higher. Application of retigabine also reversed the loss of force (rescue) for HypoPP muscle maintained in 2 mM K+. Our findings show that retigabine, a selective agonist of the KV7 family of potassium channels, is effective for the prevention of low-K+ induced attacks of weakness and to enhance recovery from an ongoing loss of force in mouse models of type 1 (Cacna1s) and type 2 (Scn4a) HypoPP. Substantial protection from the loss of force occurred in the low micromolar range, well within the therapeutic window for retigabine.
Quiñonez et al. (Mon,) conducted a other in Hypokalaemic periodic paralysis (HypoPP). Retigabine vs. Pinacidil was evaluated on Loss of force induced by a 2 mM K+ challenge. Retigabine completely prevented the loss of force induced by a 2 mM K+ challenge in mouse models of HypoPP, with IC50s of 0.8 ± 0.13 μM and 2.2 ± 0.42 μM.
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