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

• Published in: Neuroscience bulletin Vol. 30; no. 4; pp. 697 - 710
• Main Authors: Zhang, Heng, Ji, Hui, Liu, Zhirui, Ji, Yonghua, You, Xinmin, Ding, Gang, Cheng, Zhijun
• Format: Journal Article
• Language: English
• Published: Heidelberg Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences 01.08.2014
• Subjects: Anatomy; Anesthesiology; Anesthetics, Local - pharmacology; Animals; Biomedical and Life Sciences; Biomedicine; Bupivacaine - pharmacology; Cells, Cultured; Human Physiology; NAV1.5 Voltage-Gated Sodium Channel - genetics; NAV1.5 Voltage-Gated Sodium Channel - metabolism; Neurology; Neurosciences; Oocytes - metabolism; Original; Original Article; Pain Medicine; Voltage-Gated Sodium Channel Blockers - pharmacology; Xenopus laevis - genetics; Xenopus laevis - metabolism; 临床应用; 受体结合位点; 心脏; 毒性反应; 电压依赖性; 电压门控钠通道; 细胞表达; 非洲爪蟾卵母细胞; 1.5; voltage-dependent blockade; Na; bupivacaine; inactivated state
• ISSN: 1673-7067; 1995-8218; 1995-8218
• DOI: 10.1007/s12264-013-1449-1

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.