Voltage-dependent blockade by bupivacaine of cardiac sodium channels expressed in Xenopus oocytes  

作　　者：Heng Zhang Hui Ji Zhirui Liu Yonghua Ji Xinmin You Gang Ding Zhijun Cheng 

机构地区：[1]Lab of Neuropharmacology and Neurotoxicology,Shanghai University [2]Xinhua Hospital (Chongming),Shanghai Jiaotong University School of Medicine [3]Xinhua Translational Institute for Cancer Pain

出　　处：《Neuroscience Bulletin》2014年第4期697-710,共14页神经科学通报（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (31171064);the Key Research Program of Science and Technology Commissions of Shanghai Municipality (11JC1404300,13DJ1400300);with financial support from Xinhua Hospital (Chongming),Shanghai Jiaotong University School of Medicine

摘　　要：Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels （VGSCs）, how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Navl.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine- triggered arrhythmia. Here, we investigated the effect of bupivacaine on Navl.5 within the clinical concentration range. The electrophysiological measurements on Navl.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of/Na and the half-maximal inhibitory dose was 4.51 pmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Navl.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nay1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.Bupivacaine ranks as the most potent and efficient drug among class I local anesthetics, but its high potential for toxic reactions severely limits its clinical use. Although bupivacaine-induced toxicity is mainly caused by substantial blockade of voltage-gated sodium channels （VGSCs）, how these hydrophobic molecules interact with the receptor sites to which they bind remains unclear. Navl.5 is the dominant isoform of VGSCs expressed in cardiac myocytes, and its dysfunction may be the cause of bupivacaine- triggered arrhythmia. Here, we investigated the effect of bupivacaine on Navl.5 within the clinical concentration range. The electrophysiological measurements on Navl.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of/Na and the half-maximal inhibitory dose was 4.51 pmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Navl.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nay1.5 but also accelerated the development of its open-state slow inactivation. These results extend our knowledge of the action of bupivacaine on cardiac sodium channels, and therefore contribute to the safer and more efficient clinical use of bupivacaine.

关 键 词：BUPIVACAINE NAV1.5 voltage-dependentblockade inactivated state 

分 类 号：R614[医药卫生—麻醉学]