Abstract
Malignant hyperthermia (MH) is an autosomal pharmacogenetic disease triggered by volatile halogenated anesthetics and/or depolarizing muscle relaxants. An MH reaction is life-threatening and is caused by an abnormally high release of myoplasmic Ca2+ from the sarcoplasmic reticulum through the ryanodine receptor 1 (RYR1). Mutations in the RYR1 gene are the major cause of MH and central core disease (CCD). More than 200 variants of RYR1 and 3 variants of α1-subunit of the voltage-dependent L-type Ca2+ channel (CACNA1S) linked to MH and CCD have been identified, but only 30 mutations are recognized as causative for MH and/or CCD. Myotubes cultured from MH patients showed increased sensitivity to RYR1 activators (caffeine, halothane and 4-chloro-m-cresol). Halothane leads to a significant contracture in MH susceptible (MHS) skeletal muscle bundles and increases the rate of calcium-induced calcium release (CICR) in MHS skinned fibers. More recently, store-operated Ca2+ entry was reported to be activated by halothane in human MHS skeletal skinned fibers. Dantrolene, the only specific treatment for MH, reduces the elevated myoplasmic Ca2+ level generated with MH reaction, but the exact mechanism underlying its inhibitory effect is unknown. For purging volatile anesthetics, modern anesthesia workstations require more time to flush with a high-flow fresh gas (O2).
