Bumetanide prevents transient decreases in muscle force in murine hypokalemic periodic paralysis

Objective: To test the hypothesis that inhibition of the Na-K-2Cl transporter with bumetanide will reduce the susceptibility to decreases in muscle force in a mouse model of hypokalemic periodic paralysis (HypoPP). Methods: In vitro contraction tests were performed on soleus muscle isolated from mice with knock-in missense mutations that result in HypoPP (sodium channel NaV1.4-R669H) or hyperkalemic periodic paralysis (HyperPP; sodium channel NaV1.4-M1592V). Results: Bumetanide prevented the development of weakness in 2 mM K⁺ and also restored force during an established attack of HypoPP. Stimulation of the Na-K-2Cl transporter via induction of hyperosmolality exacerbated the weakness seen in low K⁺ and was also prevented by bumetanide. Bumetanide was more efficacious than acetazolamide for preventing weakness in low K⁺ conditions. Decreases in force in HyperPP muscle exposed to 10 mM K⁺ were not prevented by treatment with bumetanide. Conclusions: The Na-K-2Cl inhibitor bumetanide was highly effective in preventing attacks of weakness in the NaV1.4-R669H mouse model of HypoPP and should be considered for management of patients with HypoPP due to sodium channel mutations. Dehydration may aggravate HypoPP by stimulating the Na-K-2Cl transporter.