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 Ca2+- 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 (T90/10) were monitored. Compared to wild type, fast-twitch muscle specimen of BK-/- mice resulted in a significantly decreased T90/10 in presence of 9-AC.
Paxilline significantly shortened T90/10 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 T90/10. 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).