TY  - JOUR
A1  - Hoppe, Kerstin
A1  - Sartorius, Tina
A1  - Chaiklieng, Sunisa
A1  - Wietzorrek, Georg
A1  - Ruth, Peter
A1  - Jurkat-Rott, Karin
A1  - Wearing, Scott
A1  - Lehmann-Horn, Frank
A1  - Klingler, Werner
T1  - Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation
JF  - Frontiers in Physiology
N2  - Reduced Cl\(^{-}\) conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca\(^{2+}\)- and voltage-activated K\(^{+}\) channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK\(^{-/-}\)) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T\(_{90/10}\)) were monitored. Compared to wild type, fast-twitch muscle specimen of BK\(^{-/-}\) mice resulted in a significantly decreased T\(_{90/10}\) in presence of 9-AC. Paxilline significantly shortened T\(_{90/10}\) of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T\(_{90/10}\). The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC).
KW  - paxilline
KW  - NS1608
KW  - repetitive firing
KW  - myotonia congenita
KW  - muscle disease
KW  - BK channel
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218152
VL  - 11
ER  - 
TY  - JOUR
A1  - Klingler, Werner
A1  - Heiderich, Sebastian
A1  - Girard, Thierry
A1  - Gravino, Elvira
A1  - Heffron, James J. A.
A1  - Johannsen, Stephan
A1  - Jurkat-Rott, Karin
A1  - Rüffert, Henrik
A1  - Schuster, Frank
A1  - Snoeck, Marc
A1  - Sorrentino, Vincenzo
A1  - Tegazzin, Vincenzo
A1  - Lehmann-Horn, Frank
T1  - Functional and genetic characterization of clinical malignant hyperthermia crises: a multi-centre study
JF  - Orphanet Journal of Rare Diseases
N2  - Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. 
Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. 
Results: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. 
Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.
KW  - susceptibility
KW  - central core disease
KW  - skeletal muscle
KW  - North American
KW  - malignant hyperthermia
KW  - succinylcholine
KW  - suxamethonium
KW  - volatile anesthetics
KW  - RyR1 mutations
KW  - New Zealand
KW  - inhalation anesthetics
KW  - sarcoplasmic reticulum
KW  - ryanodine receptor gene
KW  - vitro contracture test
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117630
SN  - 1750-1172
VL  - 9
IS  - 8
ER  -