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GENERAL ARTICLES

The Differential Effect of Halothane and 1,2-Dichlorohexafluorocyclobutane on In VitroMuscle Contractures of Patients Susceptible to Malignant Hyperthermia

Christoph H. Kindler, MD^*, Thierry Girard, MD^*, Diane Gong, BS, and Albert Urwyler, MD^*

*Departments of Anesthesia and Research, University of Basel, Kantonsspital, Basel, Switzerland; and Department of Anesthesia and Perioperative Care, University of California, San Francisco, California

Address correspondence and reprint requests to Christoph H. Kindler, MD, Department of Anesthesia, University of Basel, Kantonsspital, CH-4031 Basel, Switzerland. Address e-mail to ckindler{at}uhbs.ch

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 (660 µM, equivalent to 4 minimum alveolar anesthetic concentration [MAC]) or 2N (100 µM, equivalent to 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.

IMPLICATIONS: 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.