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ANESTHETIC PHARMACOLOGY

4-Chloro-m-Cresol Cannot Detect Malignant Hyperthermia Equivocal Cells in an Alternative Minimally Invasive Diagnostic Test of Malignant Hyperthermia Susceptibility

Lukas G. Weigl, PhD^*, Carmen Ludwig-Papst, PhD, and Hans G. Kress, MD PhD^*

Departments of *Anesthesiology and Intensive Care Medicine (B) and Surgery, Medical University Vienna, Vienna, Austria

Address correspondence and reprint requests to Lukas G. Weigl, PhD, Medical University Vienna, Department of Anesthesiology and Intensive Care Medicine (B), Währinger Gürtel 18-20, A-1090 Vienna, Austria. Address e-mail to lukas.weigl{at}univie.ac.at

Malignant hyperthermia (MH) is an inherited skeletal muscle disorder triggered by commonly used anesthetics. Mutated ryanodine receptors have been identified as molecular targets. The sensitivity of myotubes from individuals classified by the in vitro contracture test as MH susceptible (MHS), normal (MHN), and equivocal (MHEH) was assessed for the Ca²⁺-releasing activity of 4-chloro-m-cresol (4-CmC) and caffeine. In this study, we sought to determine whether 4-CmC can differentiate the MH status of an individual on the basis of the release of intracellular Ca²⁺, particularly in regard to MHEH diagnosis. Intracellular Ca²⁺ concentration was determined photometrically with Fura2. Regions of the ryanodine receptor 1 harboring most of the described MH mutations were sequenced from MHS and MHEH cells. One MH mutation (Gly2434Arg) was found in one MHS individual. Results of the caffeine-induced Ca²⁺ release in MHS and MHN cells correlated well with the in vitro contracture test results. MHS cells showed a higher sensitivity against caffeine and, to a lesser extent, against 4-CmC. Cells of MHEH individuals showed low sensitivities against both caffeine and 4-CmC, comparable to those of the MHN group. Therefore, with myotubes, caffeine was able to discriminate between MHS and MHN cells, but both caffeine and 4-CmC failed to detect MHEH cells.

IMPLICATIONS: For the diagnostic test of susceptibility to malignant hyperthermia (MH), 4-chloro-m-cresol (4-CmC) has been proposed. In our study with differentiated human skeletal muscle cells, however, 4-CmC, like caffeine, could not distinguish between cells from individuals tested in the in vitro contracture test as normal and MH equivocal.