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 Ca2+-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 Ca2+-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 μM propofol. A rise of Ca2+ was not seen under 100 μM propofol and the EC50 value for propofol was 274.7±33.9 μM, which, is higher than the clinical levels for anaesthesia. Propofol-induced Ca2+ responses were remarkably attenuated in the presence of Ca2+ channel blocker or Ca2+-induced Ca2+ 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.

Effects of taurine on Ca2(+)-dependent force development of skinned muscle fibre preparations

The effects of the naturally occurring amino acid taurine (2-aminoethanesulphonic acid) on isometric force development were investigated using skinned muscle fibre preparations. In atrial and ventricular pig heart muscles, as well as in fibres of slow abdominal extensor muscle of crayfish, an increase of submaximal isometric force was observed in Ca2(+)-activated skinned fibre preparations at physiological concentrations of taurine. The maximal isometric force remained unaffected in all preparations. It is assumed that taurine increases the Ca2+ sensitivity of the force-generating myofilaments in mammalian hearts and crustacean slow skeletal muscle fibres.

Differences in temperature dependence of muscle contractile properties and myofibrillar ATPase activity in a cold-temperature fish

Single muscle fibres were isolated from the fast myotomal muscle of the teleost Myoxocephalus scorpius L. and chemically skinned with 1% Brij. Maximum Ca2+-activated force (P0) increased from 14.5 +/− 1.1 N cm-2 at 2 degrees C to 19.1 +/− 1.8 N cm-2 at 15 degrees C (mean +/− S.E.). Maximum contraction velocity was determined by Hill's slack-test method (V0) and by extrapolation from force-velocity (P-V) relationships (Vmax). There was a linear relation between log10 V0 and temperature below 15 degrees C (Q10 = 1.9, P less than 0.01). The force-velocity characteristics of the fibres were determined at 2 degrees C and 20 degrees C. Points below 0.6 P0 on the P-V curve could be fitted by a linear form of Hill's equation. Extrapolated Vmax values were 0.55 muscle lengths s-1 (L0 s-1) at 2 degrees C and 1.54 L0 s-1 at 20 degrees C. Curvature of the P-V relationship was independent of temperature. The Mg2+, Ca2+-ATPase activity of Triton-X 100 extracted myofibrils was determined under similar ionic conditions to those used in skinned fibre experiments. (Ionic strength 0.16 mmol l-1, pMgATP 2.5). A linear relationship between log10 ATPase and temperature was only obtained below 15 degrees C (P less than 0.001). Above 15 degrees C, the Q10 for ATPase decreased significantly. The Q10(0–15 degrees C) for ATPase activity (3.9) was significantly higher than for unloaded contraction velocity. Supercontraction of isolated myofibrils to very short sarcomere lengths and differences in the mechanical constraints for crossbridge cycling between the preparations probably account for the lack of proportionality between these two parameters.