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Bupivacaine-induced Apoptosis in the Primary Cultured Cardiomyocytes via p38 MAPKs
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- Authors
- Issue Date
- 2006-06
- Publisher
- 대한마치과학회
- Citation
- Kor J Anesth 2006;50:S48-56
- Keywords
- apoptosis ; bupivacaine ; calcium ; cardiomyocyte ; levobupivacaine ; mitogen-activated protein kinases
- Abstract
- Background: It is known that bupivacaine induce cell death in several immortalized cells. However, there is no report
concerning bupivacaine-induced cell death in the primary cultured cardiomyocytes. We compared the direct cytotoxicity of local
anesthetics in cardiomyocytes. Furthermore, the mechanisms of cell death were evaluated.
Methods: The myocardial cells of rat pups were cultured 3 days after seeding. The methyltetrazolium (MTT) assay was
employed to quantify differences in cellular viability. To confirm apoptosis, Hoechst-propidium iodide staining, DNA fragmentation
by electrophoresis and western blot analysis were performed. And to examine the mechanisms of cell death, intracellular calcium
and expression levels of mitogen-activated protein kinases (MAPKs) family members were evaluated.
Results: Among the local anesthetics under 1 mM concentration for 18 h, only bupivacaine significantly decreased the MTT
activity (P < 0.001). Bupivacaine induced cell death in a dose-responsive and time dependent manner. Cell death showed apoptotic
characteristics, such as DNA fragmentation, chromatin condensation, decrease of precursor caspase-3 protein level, increased cleaved
PARP, and cytochrome C release into the cytoplasm. Bupivacaine phosphorylated three major MAPKs, i.e. extracellular signalregulated
kinases (ERKs), p38 kinase and c-Jun N-terminal kinases (JNKs) stress-activated protein kinases. Administration of ERK
inhibitor increase cell death, whereas inhibitors of p38 kinase and JNK decreased cell death (P < 0.05). In addition, the intracellular
calcium level was approximately 4 times higher after the bupivacaine treatment (P < 0.001), which was inhibited by calcium
chelators (P < 0.001). Calcium chelators inhibited expression of MAPKs.
Conclusions: In bupivacaine-induced apoptosis in cardiomyocytes, intracellular calcium increase and MAPKs family plays
important roles.
- ISSN
- 2005-6419
- Language
- English
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