Propofol-induced changes in myoplasmic calcium concentrations in cultured human skeletal muscles from RYR1 mutation carriers.
Malignant hyperthermia is a pharmacogenetic disorder caused by autosomal dominant mutations in the ryanodine receptor type 1 gene. Propofol has been reported as a safe anaesthetic for malignant hyperthermia susceptible patients but has not been tested on cultured cells from patients with the ryanodine receptor type 1 mutation. The aim of this study was to determine whether propofol could trigger abnormal calcium fluxes in human myotubes isolated from malignant hyperthermia susceptible patients harbouring the native ryanodine receptor type 1 mutation. Muscle specimens were obtained from the patients to diagnose malignant hyperthermia disposition and the calcium-induced calcium release test and molecular genetic analyses were performed. Using the calcium sensitive probe Fura 2, we determined the 340/380 nm wave-length ratios by measuring alterations in calcium homeostasis in isolated myotubes from cultured skeletal muscle specimens. Two patients, one with ryanodine receptor type 1 R2508C and one with the L4838V mutation had accelerated calcium-induced calcium release rates. The 340/380 nm ratios increased when the propofol concentration exceeded 100 microM. The half-maximal activation concentrations (EC50) for propofol from patients 1 and 2 were 181.1 and 420.5 microM, respectively. Increases in calcium concentrations in response to propofol dosage were limited to doses at least 100-fold greater than those used in clinical settings. These observations correlate well with clinical observations that propofol does not trigger malignant hyperthermia in susceptible humans.
Migita
T
T
Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima, Japan.
Mukaida
K
K
Kawamoto
M
M
Kobayashi
M
M
Nishino
I
I
Yuget
O
O
D000293:Adolescent; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008967:Molecular Biology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000378:metabolism; D017354:Point Mutation; D015742:Propofol / Q000494:pharmacology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*
D018686:Anesthetics, Intravenous; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium; D015742:Propofol