Dantrolene requires Mg²⁺ to arrest malignant hyperthermia.

Abstract

Malignant hyperthermia (MH) is a clinical syndrome of skeletal muscle that presents as a hypermetabolic response to volatile anesthetic gases, where susceptible persons may develop lethally high body temperatures. Genetic predisposition mainly arises from mutations on the skeletal muscle ryanodine receptor (RyR). Dantrolene is administered to alleviate MH symptoms, but its mechanism of action and its influence on the Ca²⁺ transients elicited by MH triggers are unknown. Here, we show that Ca²⁺ release in the absence of Mg²⁺ is unaffected by the presence of dantrolene but that dantrolene becomes increasingly effective as cytoplasmic-free [Mg²⁺] (free [Mg²⁺]_cyto) passes mM levels. Furthermore, we found in human muscle susceptible to MH that dantrolene was ineffective at reducing halothane-induced repetitive Ca²⁺ waves in the presence of resting levels of free [Mg²⁺]_cyto (1 mM). However, an increase of free [Mg²⁺]_cyto to 1.5 mM could increase the period between Ca²⁺ waves. These results reconcile previous contradictory reports in muscle fibers and isolated RyRs, where Mg²⁺ is present or absent, respectively, and define the mechanism of action of dantrolene is to increase the Mg²⁺ affinity of the RyR (or "stabilize" the resting state of the channel) and suggest that the accumulation of the metabolite Mg²⁺ from MgATP hydrolysis is required to make dantrolene administration effective in arresting an MH episode.