Preclinical pharmacological in vitro investigations on low chloride conductance myotonia: effects of potassium regulatio
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MUSCLE PHYSIOLOGY
Preclinical pharmacological in vitro investigations on low chloride conductance myotonia: effects of potassium regulation Kerstin Hoppe 1,2 & Sunisa Chaiklieng 3,4 & Frank Lehmann-Horn 2 & Karin Jurkat-Rott 5 & Scott Wearing 6,8 & Werner Klingler 6,7,8 Received: 7 December 2019 / Revised: 24 May 2020 / Accepted: 26 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract In myotonia, reduced Cl− conductance of the mutated ClC-1 channels causes hindered muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. Repetitive contraction temporarily decreases myotonia, a phenomena called “warm up.” The underlying mechanism for the reduction of hyperexcitability in warm-up is currently unknown. Since potassium displacement is known to reduce excitability in, for example, muscle fatigue, we characterized the role of potassium in native myotonia congenita (MC) muscle. Muscle specimens of ADR mice (an animal model for low gCl− conductance myotonia) were exposed to increasing K+ concentrations. To characterize functional effects of potassium ion current, the muscle of ADR mice was exposed to agonists and antagonists of the big conductance Ca2+-activated K+ channel (BK) and the voltage-gated Kv7 channel. Effects were monitored by functional force and membrane potential measurements. By increasing [K+]0 to 5 mM, the warm-up phenomena started earlier and at [K+]0 7 mM only weak myotonia was detected. The increase of [K+]0 caused a sustained membrane depolarization accompanied with a reduction of myotonic bursts in ADR mice. Retigabine, a Kv7.2–Kv7.5 activator, dosedependently reduced relaxation deficit of ADR myotonic muscle contraction and promoted the warm-up phenomena. In vitro results of this study suggest that increasing potassium conductivity via activation of voltage-gated potassium channels enhanced the warm-up phenomena, thereby offering a potential therapeutic treatment option for myotonia congenita. Keywords Myotonia congenita . Warm-up phenomena . BK channel . KCNQ5 channel
Abbreviations 9-AC ADR AP BK channel
Anthracene-9-carboxylic acid Arrested development of rightening response Action potential Big conductance Ca2+-activated K+ channel
* Kerstin Hoppe [email protected] 1
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University Frankfurt, Theodor–Stern–Kai 7, 60590 Frankfurt, Germany
2
Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital of Wuerzburg, Oberduerrbacher Str. 6, 97080 Wuerzburg, Germany
3
Division of Neurophysiology in the Center of Rare Diseases, Ulm University, Albert Einstein Allee 23, 89081 Ulm, Germany
4
Faculty of Public Health, Khon Kaen University, Muang Khon Kaen, Thailand
ClC-1 DMSO EDL RMP
Skeletal muscle chloride channel type 1 Dimethylsulfoxide Extensor digitorum longus Resting membrane potential
5
Universtiy Medical Center Ulm, Division of Experimental Anesthesiology, Albert-Einstein-
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