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CRITICAL CARE AND TRAUMA

The Influence of Atracurium, Cisatracurium, and Mivacurium on the Proliferation of Two Human Cell Lines In Vitro

Anton Amann, PhD^*, Josef Rieder, MD^*, Martina Fleischer, Peter Niedermüller^*, Georg Hoffmann, PhD, Albert Amberger, PhD, Christian Marth, MD, Vladimir Nigrovic, MD^&||;, and Friedrich Pühringer, MD^¶

Departments of *Anesthesiology and Critical Care Medicine and Obstetrics and Gynecology, and D. Swarovski Research Laboratory, Department of Transplant Surgery, Leopold-Franzens-University of Innsbruck, Austria; Department of Physiology I, University of Bonn, Bonn, Germany; ||Departments of Anesthesiology and Pharmacology, Medical College of Ohio, Toledo, Ohio; and ¶Department of Anaesthesia and Intensive Care Medicine, Klinikum am Steinenberg, Reutlingen, Germany

Address correspondence and reprint requests to Dr. Anton Amann, The Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Anichstrasse 35, 6020 Innsbruck, Austria. Address e-mail to anton.amann@ uibk.ac.at.

We tested the influence of atracurium and cisatracurium (final concentrations: 0, 0.96, 3.2, 9.6, 32, and 96 µM) on proliferation of human cells (hepatoma HepG2 cells and human umbilical vein endothelial cells) in vitro. In additional experiments, glutathione, N-acetylcysteine, or carboxyl esterase was added before the addition of either relaxant. The number of cells counted after 72 h of incubation was expressed as a percentage of the mean cell number in wells incubated without additives. Atracurium and cisatracurium progressively decreased cell proliferation in a concentration-dependent pattern. With human umbilical vein endothelial cells, atracurium or cisatracurium (3.2 µM) decreased the cell count to 67.7 % (SD, 14.8%) and 50% (SD, 8.6%), respectively. Cell proliferation was not inhibited by mivacurium. The results were similar to those with HepG2 cells. Glutathione, N-acetylcysteine, and carboxyl esterase partially reversed the effects of atracurium and cisatracurium. When incubated in a buffer with glutathione, atracurium decreased the number of glutathione-sulfhydryl groups. The findings that atracurium and cisatracurium inhibit proliferation of human cell lines in vitro, but that mivacurium does not, and that this effect is alleviated by glutathione and N-acetylcysteine, as well as by the carboxyl esterase, indicate that the inhibition may be caused by the reactive acrylate metabolites.

IMPLICATIONS: We tested the influence of atracurium and cisatracurium on proliferation of human cells (hepatoma HepG2 cells and human umbilical vein endothelial cells) in vitro. Atracurium and cisatracurium progressively decreased cell proliferation in a concentration-dependent pattern, whereas cell proliferation was not inhibited, even by the largest concentration of mivacurium.

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