Phenol derivatives accelerate inactivation kinetics in one inactivation-deficient mutant human skeletal muscle Na(+) channel.
Altered inactivation kinetics in skeletal muscle Na(+) channels due to mutations in the encoding gene are causal for the alterations in muscle excitability in nondystrophic myotonia. Na(+) channel blockers like lidocaine and mexiletine, suggested for therapy of myotonia, do not reconstitute inactivation in channels with defective inactivation in vitro. We examined the effects of four methylated and/or halogenated phenol derivatives on one heterologously expressed inactivation-deficient Paramyotonia congenita-mutant (R1448H) muscle Na(+) channel in vitro. All these compounds accelerated delayed inactivation of R1448H-whole-cell currents during a depolarization and delayed accelerated recovery from inactivation. The potency of these effects paralleled the potency of the drugs to block the peak current amplitude. We conclude that the investigated phenol derivatives affect inactivation-deficient Na(+) channels more specifically than lidocaine and mexiletine. However, for all compounds, the effect on inactivation was accompanied by a substantial block of the peak current amplitude.
Haeseler
G
G
Department of Anaesthesia, OE 8050 Hannover Medical School, D-30623, Hannover, Germany. Haeseler.Gertrud@MH-Hammover.de
Piepenbrink
A
A
Bufler
J
J
Dengler
R
R
Hecker
H
H
Aronson
J
J
Piepenbrock
S
S
Leuwer
M
M
D002460:Cell Line; D002733:Chlorophenols / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D014992:Xylenes / Q000494:pharmacology
C430966:2-methyl-4-chlorophenol; D002733:Chlorophenols; D003408:Cresols; D010636:Phenols; D015222:Sodium Channels; D014992:Xylenes; C007027:chloroxylenol; C029107:4-chlorophenol; C042041:3-cresol