Mg2+ dependence of Ca2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia.

Abstract

BACKGROUND:

In normal resting muscle, cytosolic Mg(2+) exerts a potent inhibitory influence on the sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR1). Impaired Mg(2+)-regulation of RyR1 has been proposed as a causal factor in malignant hyperthermia (MH). The aim of this study was to compare the effects of cytosolic Mg(2+) on SR Ca(2+) release induced by halothane or sevoflurane in normal (MHN) and MH susceptible (MHS) human skeletal muscle fibres.

METHODS:

Samples of vastus medialis muscle were obtained from patients under investigation for MH susceptibility. Single fibres were mechanically skinned and perfused with solutions mimicking the intracellular milieu. Changes in [Ca(2+)](i) were detected using fura-2 fluorescence after application of equimolar halothane or sevoflurane.

RESULTS:

In MHN fibres, concentrations of sevoflurane or halothane as high as 10 mM typically failed to induce SR Ca(2+) release at physiological free [Mg(2+)] (1 mM). However, when [Mg(2+)] was decreased to 0.4 mM, SR Ca(2+) release occurred in 51% (16/33) and 6% (2/33) of MHN fibres after the addition of 1 mM halothane or 1 mM sevoflurane, respectively. Further decreases in [Mg(2+)] increased the proportion of responsive fibres. In the presence of 0.1 mM [Mg(2+)], Ca(2+) release occurred in all fibres (33/33) after the introduction of 1 mM halothane or 1 mM sevoflurane. In MHS fibres, 1 mM halothane or 1 mM sevoflurane-induced Ca(2+) release in 54% (7/13) or 15% (2/13) of fibres, respectively, at 1 mM Mg(2+). A decrease in [Mg(2+)] to 0.2 mM Mg(2+) was sufficient to render 100% of MHS fibres (13/13) responsive to 1 mM halothane or 1 mM sevoflurane.

CONCLUSIONS:

In both MHS and MHN fibres (i) halothane is a more potent activator of SR Ca(2+) release than sevoflurane and (ii) as with halothane, the efficacy of sevoflurane-induced SR Ca(2+) release exhibits a marked dependence on cytosolic [Mg(2+)]. The marked potentiation of SR Ca(2+) release after a moderate reduction in cytosolic [Mg(2+)] suggests that conditions which cause hypomagnesaemia will increase the probability and possibly severity of an MH event. Conversely, maintenance of a normal or slightly increased cytosolic [Mg(2+)] may reduce the probability of MH.

• Authors: A M Duke, P M Hopkins, P J Halsall, D S Steele
• Journal: British journal of anaesthesia (Br J Anaesth) Vol. 97 Issue 3 Pg. 320-8 (Sep 2006) ISSN: 0007-0912 [Print] England
• PMID: 16849381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anesthetics, Inhalation
• Methyl Ethers
• Sevoflurane
• Magnesium
• Calcium
• Halothane

Topics

• Anesthetics, Inhalation (pharmacology)
• Calcium (metabolism)
• Cytosol (metabolism)
• Halothane (pharmacology)
• Humans
• Magnesium (pharmacology, physiology)
• Malignant Hyperthermia (metabolism)
• Methyl Ethers (pharmacology)
• Muscle Fibers, Skeletal (drug effects, metabolism)
• Sarcoplasmic Reticulum (drug effects, metabolism)
• Sevoflurane
• Tissue Culture Techniques