Zhang Heng, Ji Hui, Liu Zhirui, Ji Yonghua, You Xinmin, Ding Gang, Cheng Zhijun
Lab of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai, 200444, China.
Neurosci Bull. 2014 Aug;30(4):697-710. doi: 10.1007/s12264-013-1449-1. Epub 2014 Jul 9.
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. Nav1.5 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 Nav1.5 within the clinical concentration range. The electrophysiological measurements on Nav1.5 expressed in Xenopus oocytes showed that bupivacaine induced a voltage- and concentration-dependent blockade on the peak of I Na and the half-maximal inhibitory dose was 4.51 μmol/L. Consistent with other local anesthetics, bupivacaine also induced a use-dependent blockade on Nav1.5 currents. The underlying mechanisms of this blockade may contribute to the fact that bupivacaine not only dose-dependently affected the gating kinetics of Nav1.5 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.
布比卡因是I类局部麻醉药中效力最强、效果最佳的药物，但其高毒性反应风险严重限制了其临床应用。尽管布比卡因引起的毒性主要是由电压门控钠通道（VGSCs）的大量阻滞所致，但这些疏水分子如何与它们所结合的受体位点相互作用仍不清楚。Nav1.5是心肌细胞中表达的VGSCs的主要亚型，其功能障碍可能是布比卡因引发心律失常的原因。在此，我们研究了临床浓度范围内布比卡因对Nav1.5的影响。对非洲爪蟾卵母细胞中表达的Nav1.5进行的电生理测量表明，布比卡因对INa峰值产生电压和浓度依赖性阻滞，半数最大抑制剂量为4.51μmol/L。与其他局部麻醉药一致，布比卡因也对Nav1.5电流产生使用依赖性阻滞。这种阻滞的潜在机制可能是布比卡因不仅剂量依赖性地影响Nav1.5的门控动力学，还加速了其开放状态缓慢失活的发展。这些结果扩展了我们对布比卡因对心脏钠通道作用的认识，因此有助于布比卡因更安全、更有效地用于临床。
