Effects of propofol on calcium homeostasis in human skeletal muscle.
Malignant hyperthermia is a pharmacogenetic skeletal muscle disorder of intracellular calcium (Ca2+) homeostasis with an autosomal dominant inheritance. The objective of this study was to investigate the safety of propofol by investigating its effects on calcium homeostasis and its effect sites in human skeletal muscles. Muscle specimens were obtained from 10 individuals with predisposition to malignant hyperthermia. In skinned fibre experiments, we measured the effects of propofol on the Ca(2+)-induced Ca2+ release and the uptake of Ca2+ into the sarcoplasmic reticulum. Ca2+ imaging in primary myotubes was employed to analyse propofol-mediated alternations in the Ca2+ regulation and propofol-induced Ca2+ responses in the presence of Ca2+ channel blocker or Ca(2+)-induced Ca2+ release inhibitor. Increased Ca2+ release from the sarcoplasmic reticulum and inhibition of Ca2+ uptake into the sarcoplasmic reticulum were not observed with 100 microM propofol. A rise of Ca2+ was not seen under 100 microM propofol and the EC50 value for propofol was 274.7 +/- 33.9 microM, which is higher than the clinical levels for anaesthesia. Propofol-induced Ca2+ responses were remarkably attenuated in the presence of Ca2+ channel blocker or Ca(2+)-induced Ca+ release inhibitor compared with the results obtained with caffeine. We conclude firstly that propofol is safe for individuals with predisposition to malignant hyperthermia when it is used within the recommended clinical dosage range, and secondly that its mode of action upon ryanodine receptors is likely to be different from that of caffeine.
Migita
T
T
Department of Anesthesiology and Critical Care, Hiroshima University, Hiroshima, Japan.
Mukaida
K
K
Hamada
H
H
Kobayashi
M
M
Nishino
I
I
Yuge
O
O
Kawamoto
M
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D002110:Caffeine / Q000494:pharmacology / Q000633:toxicity; D002118:Calcium / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D020022:Genetic Predisposition to Disease; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity*; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D018686:Anesthetics, Intravenous; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium; D015742:Propofol