Effects of Propofol on Calcium Homeostasis in Human Skeletal Muscle

Abstract

Malignant hyperthermia is a pharmacogenetic skeletal muscle disorder of intracellular calcium (Ca 2+) 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 Ca 2+ release and the uptake of Ca 2+ into the sarcoplasmic reticulum. Ca 2+ imaging in primary myotubes was employed to analyse propofol-mediated alternations in the Ca 2+ regulation and propofol-induced Ca 2+ responses in the presence of Ca 2+ channel blocker or Ca 2+-induced Ca 2+ release inhibitor. Increased Ca 2+ release from the sarcoplasmic reticulum and inhibition of Ca 2+ uptake into the sarcoplasmic reticulum were not observed with 100 μM propofol. A rise of Ca 2+ was not seen under 100 μM propofol and the EC 50 value for propofol was 274.7±33.9 μM, which is higher than the clinical levels for anaesthesia. Propofolinduced Ca 2+ responses were remarkably attenuated in the presence of Ca 2+ channel blocker or Ca 2+-induced Ca 2+ 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.

Prevalence of Malignant Hyperthermia and Relationship with Anesthetics in Japan

“…Whether propofol can induce MH or not remains controversial. [11][12][13] Our epidemiologic data showed a relatively low prevalence of MH in propofol users and did not support an association between propofol and MH.…”

“…It is controversial whether propofol can induce MH. [11][12][13] In this report, we verified the prevalence of MH in Japan and analyzed the relationship between the use of several drugs administered during general anesthesia and the occurrence of MH, using a nationally representative inpatient database, the Japanese Diagnosis Procedure Combination (DPC) database.…”

Analysis of Human Cultured Myotubes Responses Mediated by Ryanodine Receptor 1

“…The CICR rate was measured according to Endo's method [15][16][17][18] . In brief, bundles of skeletal muscle fibres 5 to 6 mm in width and 10 to 15 mm in length were dissected into smaller pieces, and these pieces were isolated in the relaxing solution under a stereomicroscope.…”

“…The CICR rate was defined as 'accelerated' if the CICR values were more than two standard deviations above the mean of the control patients at two or more calcium concentrations. Control CICR values were derived from 12 patients with negative IVCT according to both the protocols of the European MH Group and the North American MH Group 14,18 .…”

“…Myotubes were identified morphologically, i.e. long and narrow multinuclear cells, and calcium imaging from a single myotube was performed using the Ca 2+ -sensitive fluorescent dye Fura-2 acetooxymethyl ester (Fura-2/AM, Dojindo, Japan) as previously described 17,18 . Briefly, cells were loaded with 5 μM Fura-2/AM in HEPES buffered saline (HBSS; 130.0 mM NaCl, 5.4 mM KCl, 20 mM HEPES, 2.5 mM CaCl 2 , 1.0 mM MgCl 2 and 5.5 mM glucose at pH 7.4) for 60 minutes at 37°C.…”