利多卡因和左旋布比卡因对成熟型与幼稚型NaV1.5通道具有高效失活依赖性抑制作用
Potent Inactivation-Dependent Inhibition of Adult and Neonatal NaV1.5 Channels by Lidocaine and Levobupivacaine
局麻药（LAs）的心脏毒性作用主要是对电压门控Na+通道（NaV1.5）产生抑制。有研究表明转移性乳腺癌和结肠癌细胞中存在NaV1.5，且主要是幼稚型NaV1.5 剪接异构体（nNaV1.5）。LAs对nNaV1.5的抑制作用可减少癌症的发病和转移，其机制可能与选择性阻断nNaV1.5和/或优先作用于在癌细胞中占主导地位的失活NaV1.5有关，这有利于靶向作用癌细胞的同时保护心脏功能。本研究旨在检验利多卡因和左布比卡因对成熟型NaV1.5 剪接异构体(aNaV1.5)和幼稚型NaV1.5 剪接异构体（nNaV1.5）以及静息和失活状态的NaV1.5的影响存在差异性这一假设。
用编码aNaV1.5或nNaV1.5的cDNAs短暂转染细胞并培养，全细胞电压钳技术用于检测利多卡因和左布比卡因对HEK-293细胞的重组NaV1.5通道的作用，用电压测试方案判断去极化电位中重组NaV1.5通道被激活或灭活50%时的最大电导（分别表示为V½激活和V½失活）。
利多卡因和左旋布比卡因的IC50存在显著差异，但不影响剪接异构体的功能。利多卡因和左旋布比卡因在钳制电压为−80mV时显著抑制aNaV1.5 (IC50平均[SD]分别为: 20 [22]和1 [0.6] µM)和nNaV1.5 (IC50平均[SD]分别为: 17 [10]和3 [1.6] µM)。左旋布比卡因可引起aNaV1.5通道激活50%时的最大电导（V½激活）产生去极化偏移，且具有统计学意义（平均[SD]：从−32 [4.6] mV到−26 [8.1] mV），但对电压依赖性激活的nNaV1.5无影响。利多卡因对两种异构体的V½激活均无影响，但与aNaV1.5 相比，nNaV1.5 介导的最大电流明显降低。局麻药（LAs）和NaV1.5异构体的V½失活（约−10 mV）都发生了类似的偏移，且具有统计学意义。左旋布比卡因 (1 µM)介导的两种NaV1.5异构体从失活恢复静息的速率，均显著缓慢于利多卡因（10 µM）。当钳制电压为−80mV时，局麻药（LAs）可导致约50%的aNaV1.5 或nNaV1.5发生持续性抑制。无论钳制电压为−90mV 还是−120mV，局麻药都不会引起aNaV1.5 或nNaV1.5发生持续性阻滞，也几乎不发生永久性失活。钳制电压为−120 mV时，高浓度的利多卡因(300 µM)或左旋布比卡因(100 µM)可引起明显的持续性阻滞。
本研究表明，低浓度的局麻药（LAs）对NaV1.5呈现出失活依赖性抑制，这为局麻药（LAs）安全地应用于抑制转移性肿瘤的迁移和侵袭而不产生心脏毒性提供理论依据。
Taha E, Daniel T，et al.Potent Inactivation-Dependent Inhibition of Adult and Neonatal NaV1.5 Channels by Lidocaine and Levobupivacaine[J].Anesth Analg,2018.
OBJECTIVES The study attempted to evaluate QT, QTp (Q-Tpeak) and TpTe (Tpeak-Tend) intervals in unaffected and affected blood relatives of children with clinically confirmed LQTS as well as to determine whether the values of these repolarization parameters may be used in clinical practice.
MATERIAL AND METHODS The study group included 47 affected blood relatives (27 LQTS1 and 20 LQTS2) and 68 unaffected family members without clinically confirmed LQTS symptoms. The TpTe, QT and QTp intervals were measured manually in the lead V5 of standard ECGs and corrected using Bazett's and Fridericia's formulas.
RESULTS The RR, QT, QTp and TpTe intervals with their corrected values were significantly longer (p < 0.0001) in the affected subjects than in the unaffected subjects and, similarly, in LQTS1 and LQTS2 patients compared with the unaffected family members. The TpTe interval in LQTS2 showed only a tendency to be longer compared to LQTS1, but did not reach statistical significance (p = 0.0933). For affected blood relatives, only the TpTe interval (p < 0.0409) and QT interval, corrected with Bazett's (p < 0.0393) and Fridericia's (p < 0.0495) formulas, enabled differentiation between LQTS1 (mean TpTe = 103 ±15) and LQTS2 women (mean TpTe = 106 ±17). Moreover, there were statistically significant differences (p < 0.05) in the TpTe interval between the 6 sex subgroups: unaffected women and men as well as women and men with LQTS1 and LQTS2.
CONCLUSIONS The electrocardiographic Tpeak-Tend parameter, in addition to the QT interval, is helpful in identifying affected blood relatives of children with LQTS, particularly for the group of LQTS1 and LQTS2 women. Further studies are required to assess the clinical importance of the TpTe interval in families with long QT syndrome.
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