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Abstract
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.
GLOSSARY
- ACTZ=
- acetazolamide;
- HyperPP=
- hyperkalemic periodic paralysis;
- HypoPP=
- hypokalemic periodic paralysis
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received September 24, 2012.
- Accepted November 27, 2012.
- © 2013 American Academy of Neurology
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