Cisatracurium, but not mivacurium, induces apoptosis in human umbilical vein endothelial cells in vitro.
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 micromol 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.
Rieder
J
J
Leopold-Franzens University of Innsbruck, Department of Anesthesiology and Critical Care Medicine, Innsbruck, Austria. Josef.Rieder@uibk.ac.at
Lirk
P
P
Bodrogi
F
F
Sawires
M
M
Gruber
G
G
Hoffmann
G
G
D000931:Antidotes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001279:Atracurium / Q000494:pharmacology*; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D000077590:Mivacurium; D003473:Neuromuscular Nondepolarizing Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects
D000931:Antidotes; D007546:Isoquinolines; D003473:Neuromuscular Nondepolarizing Agents; D001279:Atracurium; D000077590:Mivacurium; D005978:Glutathione