Malignant hyperthermia (MH) is an autosomal dominant, potentially fatal pharmacogenetic disorder of skeletal muscle. Approximately half of all known MH families show a linkage to the ryanodine receptor type 1 (RY1) gene. Although our knowledge of the diagnosis, genetics, and therapy of MH has improved, the exact pathogenesis and the role of volatile anesthetics as trigger substances for an MH crisis remain unknown. Compounds that do not obey the Meyer-Overton hypothesis (i.e., nonimmobilizers) are today an important part of research on anesthetic mechanisms. We designed this study to test the hypothesis that the nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N) compared with halothane has different effects on in vitro muscle contractures of muscle bundles from MH-susceptible (MHS) individuals. In vitro muscle contracture tests were performed with either halothane (approximately 660 microM, equivalent to approximately 4 minimum alveolar anesthetic concentration [MAC]) or 2N ( approximately 100 microM, equivalent to approximately 5 times predicted MAC). MAC is defined as the anesthetic concentration that prevents nocifensive movements after a surgical stimulus in 50% of subjects. In contrast to halothane, 2N caused only minimal muscle contractures in muscle bundles from six MHS patients (0.13 g [0.04-0.31 g] vs 1.95 g [1.60-4.70 g], median values and ranges; P = 0.004). Halothane and 2N differ in their effects on muscle contractures of MHS individuals, possibly because of a differing action on MH RY1. CONCLUSIONS Using in vitro contracture tests, we showed that halothane and the nonimmobilizer 1,2-dichlorohexafluorocyclobutane differ in their effects on contractures of muscle bundles from individuals susceptible to malignant hyperthermia (MH) as a result of their differing action on MH ryanodine receptors. These findings render this receptor a possible molecular target for volatile anesthetic action.