Schwoerer Alexander P, Scheel Hanno, Friederich Patrick
From the *Department of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, DZHK (German Centre for Cardiovascular Research)-Hamburg/Kiel/Luebeck, Hamburg, Germany; †Department of Anesthesiology, German Armed Forces Hospital Hamburg, Academic Hospital of University Medical Center Hamburg-Eppendorf, Hamburg, Germany; and ‡Department of Anaesthesiology, Bogenhausen Hospital, Academic Hospital of Technische Universitaet Muenchen, Munich, Germany.
Anesth Analg. 2015 Jun;120(6):1226-34. doi: 10.1213/ANE.0000000000000646.
Intoxication with local anesthetics may induce cardiac arrhythmias by interaction with ion channels. Ropivacaine has been introduced into clinical anesthesia as a safer alternative to bupivacaine, which is associated with a relatively high risk of cardiac arrhythmias. Diverging safety profiles may result from differences in the mode of interaction with cardiac Na(+) channels. We conducted this study to test this hypothesis and to provide experimental basis for the ongoing discussion regarding the cardiotoxic profiles of these local anesthetics.
The influence of bupivacaine and ropivacaine on the electrophysiological properties of Na(+) channels was investigated in human embryonic kidney-293 cells stably transfected with SCN5A channels cloned from the human heart using the patch-clamp technique in the outside-out configuration.
Open-channel block of SCN5A channels was concentration dependent, with bupivacaine being approximately 4.5-fold more potent than ropivacaine (IC50 = 69.5 ± 8.2 μM vs IC50 = 322.2 ± 29.9 μM). Both drugs influenced the voltage dependency of channel activation and steady-state inactivation by shifting the membrane potential of half-maximal activation/inactivation toward somewhat more negative membrane potentials. In their inactivated state, SCN5A channels were slightly more sensitive toward bupivacaine than toward ropivacaine (IC50 = 2.18 ± 0.16 μM vs IC50 = 2.73 ± 0.27 μM). Blockade of inactivated channels developed in a concentration-dependent manner, with comparable time constants for both drugs, whereas recovery from block was approximately 2-fold faster for ropivacaine than for bupivacaine.
Human cardiac Na(+) channels show state-dependent inhibition by ropivacaine, and the mode of interaction is comparable to that of bupivacaine. Therefore, modest differences in cardiotoxicity between these local anesthetic drugs are compatible with subtle differences in their interaction with human cardiac Na(+) channels.
局部麻醉药中毒可能通过与离子通道相互作用诱发心律失常。罗哌卡因已作为布比卡因的一种更安全替代品引入临床麻醉，布比卡因与相对较高的心律失常风险相关。不同的安全性可能源于与心脏钠通道相互作用方式的差异。我们进行这项研究以验证这一假设，并为当前关于这些局部麻醉药心脏毒性特征的讨论提供实验依据。
采用膜片钳技术的外翻式配置，在稳定转染有人心脏克隆的SCN5A通道的人胚肾-293细胞中，研究布比卡因和罗哌卡因对钠通道电生理特性的影响。
SCN5A通道的开放通道阻滞呈浓度依赖性，布比卡因的效力约为罗哌卡因的4.5倍（半数抑制浓度[IC50]=69.5±8.2μM对IC50=322.2±29.9μM）。两种药物均通过将半数最大激活/失活的膜电位向更负的膜电位偏移来影响通道激活和稳态失活的电压依赖性。在失活状态下，SCN5A通道对布比卡因的敏感性略高于罗哌卡因（IC50=2.18±0.16μM对IC50=2.73±0.27μM）。失活通道的阻滞呈浓度依赖性发展，两种药物的时间常数相当，而罗哌卡因从阻滞中恢复的速度约为布比卡因的2倍。
人心脏钠通道对罗哌卡因表现出状态依赖性抑制，且相互作用方式与布比卡因相当。因此，这些局部麻醉药之间心脏毒性的适度差异与它们与人心脏钠通道相互作用的细微差异相符。
