A novel saline-soluble, rapidly-metabolized RyR1 inhibitor rescues volatile anesthesia-induced death and environmental heat stroke in a mouse model relevant to malignant hyperthermia

Mutations in the type 1 ryanodine receptor (RyR1), a Ca2+ release channel in skeletal muscle, hyperactivate the channel to cause malignant hyperthermia (MH) and are implicated in severe heat stroke. Dantrolene, the only approved drug for MH, has the disadvantages of having very poor water solubility and long plasma half-life. We show here that a novel RyR1-selective inhibitor, 6,7-(methylenedioxy)-1-octyl-4-quinolone-3-carboxylic acid (Compound 1), effectively rescues MH and heat stroke in several mouse models relevant to MH. Compound 1 reduced resting intracellular Ca2+, inhibited halothane-induced Ca2+ release, suppressed caffeine-induced contracture in skeletal muscle, reduced sarcolemmal cation influx, and prevented or reversed the fulminant MH crisis by isoflurane anesthesia and heat stroke by environmental heat stress. Notably, Compound 1 has great advantages of better water solubility and rapid clearance in vivo over dantrolene. Compound 1 has the potential to be a promising new candidate for effective treatment of patients carrying RyR1 mutations.