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Korean J Anesthesiol > Volume 50(6); 2006 > Article
Korean Journal of Anesthesiology 2006;50(6):S48-S56.
DOI: https://doi.org/10.4097/kjae.2006.50.6.S48   
Bupivacaine-induced Apoptosis in the Primary Cultured Cardiomyocytes via p38 MAPKs.
Hyun Jeong Kim, Se Ra Sung, Kwang Suk Seo, Seung Woon Lim, Tae Gyoon Yoon
1Department of Dental Anesthesiology, Seoul National University College of Dentistry, Seoul, Korea.
2Department of Anesthesiology and Pain Medicine, Chungbuk National University College of Medicine, Cheongju, Korea.
3Department of Anesthesiology and Pain Medicine, Seoul National University College of Medicine, Seoul, Korea. ytg001@dreamwiz.com
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.
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.
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 signal-regulated 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.
In bupivacaine-induced apoptosis in cardiomyocytes, intracellular calcium increase and MAPKs family plays important roles.
Key Words: apoptosis; bupivacaine; calcium; cardiomyocyte; levobupivacaine; mitogen-activated protein kinases
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