Hostname: page-component-586b7cd67f-t7fkt Total loading time: 0 Render date: 2024-11-26T14:31:47.575Z Has data issue: false hasContentIssue false
  • English
  • Français

Cisatracurium, but not mivacurium, induces apoptosis in human umbilical vein endothelial cells in vitro

Published online by Cambridge University Press:  13 April 2005

J. Rieder ,
P. Lirk ,
F. Bodrogi ,
M. Sawires ,
G. Gruber  and
G. Hoffmann
J. Rieder
Affiliation:
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria
P. Lirk
Affiliation:
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria
F. Bodrogi
Affiliation:
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria
M. Sawires
Affiliation:
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria
G. Gruber
Affiliation:
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria
G. Hoffmann
Affiliation:
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria
Get access

Extract

Summary

Background and objective: Cisatracurium is an intermediate acting, non-depolarizing neuromuscular blocking agent. Previous reports have indicated a growth-inhibitory effect of the isoforms cisatracurium and atracurium on two human cell lines in vitro. These effects were ascribed to oxidative stress elicited by acrylate esters formed during cisatracurium breakdown. Oxidative stress is a potent precipitator of apoptosis. Therefore, the aim of the present study was to investigate whether the growth-inhibitory effects of cisatracurium could be explained by initiation of apoptosis.

Methods: Human umbilical vein endothelial cells were incubated with cisatracurium at concentrations of 0.96, 3.2, 9.6, 32 and 96 μmol for 24 h. DNA fragmentation was measured using the Cell Death Detection ELISA Plus assay (Roche Diagnostics, Mannheim, Germany).

Results: There was a dose dependency of cisatracurium with respect to the rate of apoptosis in human umbilical vein endothelial cells. Programmed cell death could be demonstrated at concentrations encountered in human plasma after single-bolus injections of cisatracurium. Apoptosis was attenuated by the concomitant administration of glutathione.

Conclusions: These findings strongly support the hypothesis that acrylate esters, breakdown products of cisatracurium, induce oxidative stress and, subsequently, apoptosis.

Keywords

NEUROMUSCULAR BLOCKING AGENTS, cisatracurium, mivacurium, breakdown productsGLUTATHIONEENDOTHELIAL CELLS, human umbilical venousOXIDATIVE STRESSAPOPTOSIS
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 22 , Issue 1 , January 2005 , pp. 16 - 19
Copyright
© 2005 European Society of Anaesthesiology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Ward S, Neill EA. Pharmacokinetics of atracurium in acute hepatic failure (with acute renal failure). Br J Anaesth 1983; 55: 1169–1172.Google Scholar
Amann A, Rieder J, Fleischer M, et al. The influence of atracurium, cisatracurium, and mivacurium on the proliferation of two human cell lines in vitro. Anesth Analg 2001; 93: 690–696.Google Scholar
Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today 1994; 15: 7–10.Google Scholar
Neill EA, Chapple DJ, Thompson CW. Metabolism and kinetics of atracurium: an overview. Br J Anaesth 1983; 55: 23S–25S.Google Scholar
Nigrovic V, Banoub M. Pharmacokinetic modelling of a parent drug and its metabolite. Atracurium and laudanosine. Clin Pharmacokinet 1992; 22: 396–408.Google Scholar
Nigrovic V, Klaunig JE, Smith SL, Schultz NE. Potentiation of atracurium toxicity in isolated rat hepatocytes by inhibition of its hydrolytic degradation pathway. Anesth Analg 1987; 66: 512–516.Google Scholar
Moore MM, Amtower A, Doerr CL, Brock KH, Dearfield KL. Genotoxicity of acrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and ethyl methacrylate in L5178Y mouse lymphoma cells. Environ Mol Mutagen 1988; 11: 49–63.Google Scholar
Dearfield KL, Millis CS, Harrington-Brock K, Doerr CL, Moore MM. Analysis of the genotoxicity of nine acrylate/ methacrylate compounds in L5178Y mouse lymphoma cells. Mutagenesis 1989; 4: 381–393.Google Scholar
Sorooshian SS, Stafford MA, Eastwood NB, et al. Pharmacokinetics and pharmacodynamics of cisatracurium in young and elderly adult patients. Anesthesiology 1996; 84: 1083–1091.Google Scholar
Nigrovic V, Auen M, Wajskol A. Enzymatic hydrolysis of atracurium in vivo. Anesthesiology 1985; 62: 606–609.Google Scholar
Kintz P, Tracqui A, Ludes B. The distribution of laudanosine in tissues after death from atracurium injection. Int J Legal Med 2000; 114: 93–95.Google Scholar
Beemer GH, Dennis WL, Platt PR, Bjorksten AR, Carr AB. Adverse reactions to atracurium and alcuronium. A prospective surveillance study. Br J Anaesth 1988; 61: 680–684.Google Scholar
Caldwell JE, Lau M, Fisher DM. Atracurium versus vecuronium in asthmatic patients. A blinded, randomized comparison of adverse events. Anesthesiology 1995; 83: 986–991.Google Scholar
Reckendorfer H, Burgmann H, Sperlich M, et al. Hepatotoxicity testing of atracurium and laudanosine in the isolated, perfused rat liver. Br J Anaesth 1992; 69: 288–291.Google Scholar
Sperlich M, Reckendorfer H, Burgmann H, et al. Altered hepatic function by atracurium or its breakdown products. Transplant Proc 1993; 25: 1851–1852.Google Scholar
Burgmann H, Reckendorfer H, Sperlich M, et al. Influence of incubated atracurium on rat liver function. Br J Anaesth 1994; 72: 324–327.Google Scholar
Casey W, Anderson S, Fox T, et al. Transcriptional and physiological responses of HepG2 cells exposed to diethyl maleate: time course analysis. Physiol Genomics 2002; 28: 115–122.Google Scholar
Clarkson A, Choonara I, Martin P. Suspected toxicity of atracurium in the neonate. Paediatr Anaesth 2001; 11: 631–632.Google Scholar
Rieder J, Lirk P. Neonatal atracurium toxicity may be explained by atracurium moieties. Pediatr Anaesth 2002; 12: 656–657.Google Scholar