The anesthetic propofol modulates gating in paramyotonia congenita mutant muscle sodium channels.
We examined the effects of propofol on a paramyotonia congenita mutant skeletal muscle sodium channel in vitro, because life-threatening complications resulting from severe muscle rigidity during induction of anesthesia have been observed using other anesthetics in patients with hereditary sodium channel myopathies. Our hypothesis was that propofol might interact directly with mutant channels, causing enhanced muscle excitability in affected patients. Whole-cell voltage-clamp experiments were performed on HEK 293 cells expressing R1448H mutant sodium channels. Propofol blocked sodium inward current at clinical concentrations (5 micromol/L) when depolarizing pulses were started from holding potentials close to the physiological resting potential (-70 mV). Higher propofol concentrations (>/=25 micromol/L) accelerated pathologically delayed inactivation kinetics and delayed pathologically enhanced recovery from inactivation. Our in vitro results show that inactivation-deficient sodium channels are specifically targeted and blocked by propofol. This might reduce enhanced muscle excitability experienced by affected patients in vivo.
Haeseler
G
G
Department of Anesthesiology, OE8050, Hannover Medical School, D-30623 Hannover, Germany. haeseler@gertrud@mh-hannover.de
Störmer
M
M
Mohammadi
B
B
Bufler
J
J
Dengler
R
R
Piepenbrock
S
S
Leuwer
M
M
D019943:Amino Acid Substitution; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D018482:Muscle, Skeletal / Q000503:physiopathology; D020967:Myotonic Disorders / Q000235:genetics* / Q000503:physiopathology*; D015742:Propofol / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D014162:Transfection
D018686:Anesthetics, Intravenous; D011994:Recombinant Proteins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D015742:Propofol