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

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.

• Authors: Fenfen Wu, Wentao Mi, Stephen C Cannon
• Journal: Neurology (Neurology) Vol. 80 Issue 12 Pg. 1110-6 (Mar 19 2013) ISSN: 1526-632X [Electronic] United States
• PMID: 23427324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Bumetanide

Topics

• Animals
• Bumetanide (pharmacology, therapeutic use)
• Female
• Gene Knock-In Techniques
• Hypokalemic Periodic Paralysis (physiopathology, prevention & control)
• Male
• Mice
• Mice, Transgenic
• Muscle Contraction (drug effects, physiology)
• Muscle, Skeletal (drug effects, physiology)
• Mutation, Missense (physiology)
• Organ Culture Techniques