F HypoPP in humans, plus the sodium channel mutation NaV1.4-R
F HypoPP in humans, plus the sodium channel mutation NaV1.4-R669H. The advantageous impact of bumetanide on muscle force in low K + was sustained for up to 30 min immediately after washout (Fig. 1B) and was also associated with an overshoot upon return to typical K + (Figs 1B and 3). We attribute these sustained effects towards the slow price of myoplasmic Cl enhance upon removal of NKCC inhibition. Conversely, bumetanide was of no benefit in our mouse model of HyperPP (NaV1.4M1592V; Wu et al., 2013), which includes a completely unique pathomechanism arising from a disruption of channel inactivation (Cannon and Strittmatter, 1993). Taken together, these studies of bumetanide on mouse models of periodic paralysis add to theBrain 2013: 136; 3766|growing body of proof that HypoPP arising from mutations of CaV1.1 and NaV1.four share a common pathomechanism for paradoxical depolarization with hypokalaemia, driven by an anomalous leakage current via the voltage-sensor and modified by the Cl gradient. Despite the fact that bumetanide was powerful in preventing the loss of force in murine HypoPP caused by mutations in either CaV1.1 or NaV1.four, there have been consistent differences that might effect the clinical use of this drug. The recovery of contractile force in vitro, when bumetanide was added 20 min immediately after the onset of weakness in two mM K + , was only partial for CaV1.1-R528H + /m (Fig. 1B) whereas complete recovery occurred for NaV1.4- R669H + /m. This suggests the usage of bumetanide to abort an established attack of weakness might have higher prospective for success in NaV1.4HypoPP than CaV1.1-HypoPP.AcknowledgementsThe authors thank Hillery Gray for delivering technical help with mouse breeding and genotyping.FundingThis operate was supported by the Muscular Dystrophy Association (MDA 135815 to S.C.), by an ARRA Supplement to Grant AR42703 (S.C.) and Grant AR-063182 (S.C.) from NIAMS with the National Institutes of Overall health.Supplementary materialSupplementary material is readily available at Brain online.
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