Molecular mechanisms of the inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on sarcolemmal adenosine triphosphate-sensitive potassium channels in the cardiovascular system
Molecular mechanisms of the inhibitory effects of bupivacaine, levobupivacaine, and ropivacaine on sarcolemmal adenosine triphosphate-sensitive potassium channels in the cardiovascular system
复制标题
DOI：
10.1097/00000542-200408000-00020
复制
发表时间：
2004-08-01
期刊：
影响因子：
8.8
通讯作者：
Nakaya, Y
中科院分区：
文献类型：
--
作者：
Kawano, T;Oshita, S;Nakaya, Y
背景心血管系统中的肌膜三磷酸腺苷敏感性钾（K-ATP）通道可能参与布比卡因诱导的心血管毒性。作者研究了局麻药对内向整流钾通道编码的重构K-ATP通道活性的影响（Kir6.0）和磺酰脲受体（SUR）亚单位。作者使用由内而外的膜片钳配置来研究布比卡因、左布比卡因和罗哌卡因对在COS-7细胞中表达的重建的K-ATP通道活性的影响，结果：布比卡因立体选择性地抑制心脏K-ATP通道的活性（IC 50 = 52 μ m）（左布比卡因，IC 50 = 168 μ m;罗哌卡因，IC 50 = 249 μ m）。局部麻醉药也立体选择性地抑制Kir6.2的截断异构体（Kir6.2DeltaC36）形成的通道的活性。Kir6.2第二跨膜结构域胞质末端的突变显著降低了局麻药的亲和力和立体选择性。局部麻醉剂阻断心脏K-ATP通道的效力比血管K-ATP通道高约8倍;效力取决于SUR亚型。SUR 2A的C-末端尾部的42个氨基酸残基增强了布比卡因对Kir6.0亚基的抑制作用，而SUR 1或SUR 2B则没有。结论：局麻药对心血管系统K-ATP通道的抑制作用具有（1）立体选择性：布比卡因比左旋布比卡因和罗哌卡因更有效;（2）组织特异性：局部麻醉剂分别通过Kir6.0亚基的细胞内孔口和SUR 2A亚基C-末端尾部的42个氨基酸阻断心脏K-ATP通道比血管K-ATP通道更有效。
Background. Sarcolemmal adenosine triphosphate-sensitive potassium (K-ATP) channels in the cardiovascular system may be involved in bupivacaine-induced cardiovascular toxicity. The authors investigated the effects of local anesthetics on the activity of reconstituted K-ATP channels encoded by inwardly rectifying potassium channel (Kir6.0) and sulfonylurea receptor (SUR) subunits.Methods: The authors used an inside-out patch clamp configuration to investigate the effects of bupivacaine, levobupivacaine, and ropivacaine on the activity of reconstituted K-ATP channels expressed in COS-7 cells and containing wild-type, mutant, or chimeric SURs.Results: Bupivacaine inhibited the activities of cardiac K-ATP channels (IC50 = 52 mum) stereoselectively (levobupivacaine, IC50 = 168 mum; ropivacaine, IC50 = 249 mum). Local anesthetics also inhibited the activities of channels formed by the truncated isoform of Kir6.2 (Kir6.2DeltaC36) stereoselectively. Mutations in the cytosolic end of the second transmembrane domain of Kir6.2 markedly decreased both the local anesthetics' affinity and stereoselectivity. The local anesthetics blocked cardiac K-ATP channels with approximately eightfold higher potency than vascular K-ATP channels; the potency depended on the SUR subtype. The 42 amino acid residues at the C-terminal tail of SUR2A, but not SUR1 or SUR2B, enhanced the inhibitory effect of bupivacaine on the Kir6.0 subunit.Conclusions: Inhibitory effects of local anesthetics on K-ATP channels in the cardiovascular system are (1) stereoselective: bupivacaine was more potent than levobupivacaine and ropivacaine; and (2) tissue specific: local anesthetics blocked cardiac K-ATP channels more potently than vascular K-ATP channels, via the intracellular pore mouth of the Kir6.0 subunit and the 42 amino acids at the C-terminal tail of the SUR2A subunit, respectively.