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Dantrolene requires Mg2+ to arrest malignant hyperthermia
Rocky H Choi1, Xaver Koenig1, Bradley S Launikonis2
1School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia.
Summary
Dantrolene effectiveness in treating malignant hyperthermia (MH) depends on magnesium levels. Increased cytoplasmic magnesium enhances dantrolene
Area of Science:
- Biochemistry
- Physiology
- Pharmacology
Background:
- Malignant hyperthermia (MH) is a life-threatening hypermetabolic skeletal muscle response to anesthetics.
- Genetic mutations in the ryanodine receptor (RyR) predispose individuals to MH.
- Dantrolene is a treatment for MH, but its mechanism of action is unclear.
Purpose of the Study:
- To investigate the mechanism of dantrolene's action in malignant hyperthermia.
- To determine the influence of magnesium on dantrolene's efficacy.
- To clarify dantrolene's effect on Ca2+ transients in MH-susceptible muscle.
Main Methods:
- Studied Ca2+ release from RyR channels in the presence and absence of Mg2+.
- Examined dantrolene's effect on halothane-induced Ca2+ waves in MH-susceptible human muscle.
- Varied cytoplasmic-free Mg2+ concentrations to assess Mg2+ influence.
Main Results:
- Dantrolene's efficacy increases with cytoplasmic-free Mg2+ levels.
- Dantrolene did not affect Ca2+ release without Mg2+.
- Elevating Mg2+ to 1.5 mM increased the interval between halothane-induced Ca2+ waves in MH muscle.
Conclusions:
- Dantrolene's mechanism involves increasing the Mg2+ affinity of the RyR.
- Mg2+ accumulation from MgATP hydrolysis is necessary for dantrolene to effectively treat MH.
- Results reconcile conflicting data on dantrolene's action in different experimental conditions.