Effects of a quaternary bupivacaine derivative on delayed rectifier K(+) currents.
Effects of a quaternary bupivacaine derivative on delayed rectifier K(+) currents.
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四元布比卡因衍生物对延迟整流器 K( ) 电流的影响。
DOI：
10.1038/sj.bjp.0703334
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发表时间：
2000
影响因子：
7.3
通讯作者：
Valenzuela,C
中科院分区：
文献类型：
--
作者：
Longobardo,M;González,T;Navarro-Polanco,R;Caballero,R;Delpón,E;Tamargo,J;Snyders,DJ;Tamkun,MM;Valenzuela,C
R-布比卡因对hKv1.5通道的阻断归因于药物的带电形式与细胞内受体的相互作用。然而，布比卡因在细胞外和细胞内都是中性和带电形式的混合物。我们使用膜片钳技术的全细胞构型研究了四元布比卡因衍生物的R（+）对映体N-甲基布比卡因（RB+1C）对Ltk −细胞中稳定表达的hKv 1.5通道的影响。当从细胞膜的细胞内侧施加时，RB+1C诱导的时间和电压依赖性阻滞与R-布比卡因诱导的阻滞相似。50 μMRB+1C可使+60 mV电流降低24±2%（n=10），但这种阻滞不具有时间和电压依赖性，可部分缓解R-布比卡因引起的阻滞（61±2%vs56± 3%，n =4，P<0.05），但不能缓解内部RB+1C引起的阻滞。 此外，它不诱导使用依赖性阻滞，但当与内部RB+1C联合应用时，观察到随脉冲持续时间增加的使用依赖性阻滞。这些结果表明，RB+1C从膜的内部或细胞外侧应用时，对hKv1.5通道诱导不同的效应，这表明布比卡因的作用是在hKV 1.5通道的外侧和内侧上诱导的作用的结果. BritishJournalofPharmacology（2000）130，391-401; doi：10.1038/sj.bjp.0703334
Block of hKv1.5 channels by R‐bupivacaine has been attributed to the interaction of the charged form of the drug with an intracellular receptor. However, bupivacaine is present as a mixture of neutral and charged forms both extra‐ and intracellularly.We have studied the effects produced by the R(+) enantiomer of a quaternary bupivacaine derivative, N‐methyl‐bupivacaine, (RB+1C) on hKv1.5 channels stably expressed inLtk−cells using the whole‐cell configuration of the patch‐clamp technique.When applied from the intracellular side of the membrane, RB+1C induced a time‐ and voltage‐dependent block similar to that induced by R‐bupivacaine. External application of 50 μMRB+1C reduced the current at +60 mV by 24±2% (n=10), but this block displayed neither time‐ nor voltage‐dependence.External RB+1C partially relieved block induced by R‐bupivacaine (61±2%vs56±3%,n=4,P<0.05), but it did not relieve block induced by internal RB+1C. In addition, it did not induce use‐dependent block, but when applied in combination with internal RB+1C a use‐dependent block that increased with pulse duration was observed.These results indicate that RB+1C induces different effects on hKv1.5 channels when applied from the intra or the extracellular side of the membrane, suggesting that the actions of bupivacaine are the resulting of those induced on the external and the internal side of hKv1.5 channels.British Journal of Pharmacology(2000)130, 391–401; doi:10.1038/sj.bjp.0703334