Left Ventricular Hypertrophy Increases Susceptibility to Bupivacaine-induced Cardiotoxicity through Overexpression of Transient Receptor Potential Canonical Channels in Rats
Left Ventricular Hypertrophy Increases Susceptibility to Bupivacaine-induced Cardiotoxicity through Overexpression of Transient Receptor Potential Canonical Channels in Rats
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DOI：
10.1097/aln.0000000000003554
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发表时间：
2020-11-01
期刊：
影响因子：
8.8
通讯作者：
Nishikawa，Kiyonobu
中科院分区：
文献类型：
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作者：
Hino，Hideki;Matsuura，Tadashi;Nishikawa，Kiyonobu
背景：局部麻醉剂，特别是长效强效的布比卡因，可通过抑制钠离子通道而引起心脏毒性；然而，左心室肥厚对心脏毒性的影响及其潜在机制尚不清楚。瞬时受体电位规范（TRPC）通道在左心室肥厚中上调。据报道，一些瞬时受体电位通道亚型可以通过相对较大的阳离子，包括质子化局麻药；这就是所谓的“孔隙现象”。作者推测，由于TRPC通道上调，布比卡因引起的左心室肥厚的心脏毒性更为严重。方法采用改良的主动脉横缩模型作为左室肥厚模型。比较布比卡因对假手术和主动脉收缩雄性大鼠的心脏毒性，并通过记录心肌细胞中钠离子通道电流和TRPC蛋白的免疫细胞化学来探讨其可能的机制。结果尽管布比卡因的血药浓度较低，但主动脉收缩大鼠（n =11）的心脏骤停时间比假手术大鼠（n = 12）短（平均±SD， 1,302±324 s比1,034±211 s; P = 0.030）。布比卡因对钠离子电流的半最大抑制浓度分别为4.5 μM和4.3 μM，与TRPC3通道激活剂1-油基-2-乙酰基- cn -甘油共应用后，布比卡因对钠离子电流的半最大抑制浓度分别降至3.9 μM和2.6 μM。在两组中，钠离子电流均不受QX-314的影响，QX-314是一种带正电荷的利多卡因衍生物，几乎不渗透细胞膜，但QX-314与1-油基-2-乙酰基- cn -甘油共施用时，钠离子电流显著降低（假手术：对照组的79±10%；P = 0.004；主动脉收缩：对照组的47±27%；P = 0.020; n = 5个细胞/组）。一种特异性TRPC3通道抑制剂可拮抗1-油基-2-乙酰基-sn-甘油的作用。结论左室肥厚加重了布比卡因诱导的心脏毒性，这可能是左室肥厚中TRPC3通道“孔隙现象”上调的结果。
BackgroundLocal anesthetics, particularly potent long acting ones such as bupivacaine, can cause cardiotoxicity by inhibiting sodium ion channels; however, the impact of left ventricular hypertrophy on the cardiotoxicity and the underlying mechanisms remain undetermined. Transient receptor potential canonical (TRPC) channels are upregulated in left ventricular hypertrophy. Some transient receptor potential channel subtypes have been reported to pass relatively large cations, including protonated local anesthetics; this is known as the “pore phenomenon.” The authors hypothesized that bupivacaine-induced cardiotoxicity is more severe in left ventricular hypertrophy due to upregulated TRPC channels.MethodsThe authors used a modified transverse aortic constriction model as a left ventricular hypertrophy. Cardiotoxicity caused by bupivacaine was compared between sham and aortic constriction male rats, and the underlying mechanisms were investigated by recording sodium ion channel currents and immunocytochemistry of TRPC protein in cardiomyocytes.ResultsThe time to cardiac arrest by bupivacaine was shorter in aortic constriction rats (n =11) than in sham rats (n = 12) (mean ± SD, 1,302 ± 324 s vs. 1,034 ± 211 s; P = 0.030), regardless of its lower plasma concentration. The half-maximal inhibitory concentrations of bupivacaine toward sodium ion currents were 4.5 and 4.3 μM, which decreased to 3.9 and 2.6 μM in sham and aortic constriction rats, respectively, upon coapplication of 1-oleoyl-2-acetyl-sn-glycerol, a TRPC3 channel activator. In both groups, sodium ion currents were unaffected by QX-314, a positively charged lidocaine derivative, that hardly permeates the cell membrane, but was significantly decreased with QX-314 and 1-oleoyl-2-acetyl-sn-glycerol coapplication (sham: 79 ± 10% of control; P = 0.004; aortic constriction: 47± 27% of control; P = 0.020; n = 5 cells per group). Effects of 1-oleoyl-2-acetyl-sn-glycerol were antagonized by a specific TRPC3 channel inhibitor.ConclusionsLeft ventricular hypertrophy exacerbated bupivacaine-induced cardiotoxicity, which could be a consequence of the “pore phenomenon” of TRPC3 channels upregulated in left ventricular hypertrophy.