• Christoph Plank, Petra Hofmann, Michael Gruber, Gabriele Bollwein, Bernhard M Graf, Wolfgang Zink, and Thomas Metterlein.
• From the *Department of Anesthesiology, University Hospital Regensburg, Regensburg, Germany; and †Department of Anesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Ludwigshafen, Germany.
• Anesth. Analg. 2016 Feb 1; 122 (2): 418-23.

BackgroundLocal anesthetics, especially bupivacaine, have myotoxic effects in clinically used concentrations and context. Detailed mechanisms of these effects are unknown, but an increase in intracellular calcium levels is suspected to be the most important trigger. Dantrolene and caffeine modify cellular calcium release from the sarcoplasmic reticulum. The aim of our study was to investigate the effect of dantrolene and caffeine on bupivacaine-induced myotoxicity in vitro.MethodsA cell culture model of primary muscle cells of BALB/c AnNCrl mice was established. Cells were incubated simultaneously with increasing concentrations of bupivacaine, dantrolene, and caffeine. The fraction of dead cells was calculated after staining with propidium iodide and analysis by flow cytometry. The half-maximal inhibitory concentration of bupivacaine was calculated for each concentration. Group differences were determined by using 1-way analysis of variances with subsequent post hoc 1-way Dunnett t test.ResultsBoth dantrolene and caffeine alone had no effect on muscle cell survival. Increasing concentrations of bupivacaine caused increasing cell death. Dantrolene dose-dependently reduced the fraction of necrotic cells, whereas caffeine dose-dependently increased the fraction of dead cells.ConclusionsDantrolene attenuated, and caffeine enhanced, bupivacaine-induced myotoxicity, presumably by modifying sarcoplasmic calcium release. This indicates that intracellular calcium release is an important factor for local anesthetic-induced cell death.

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