Increasing Membrane Interactions of Local Anaesthetics as Hypothetic Mechanism for Their Cardiotoxicity Enhanced by Myocardial Ischaemia
Increasing Membrane Interactions of Local Anaesthetics as Hypothetic Mechanism for Their Cardiotoxicity Enhanced by Myocardial Ischaemia
复制标题
局部麻醉药的膜相互作用增加作为心肌缺血增强其心脏毒性的假设机制
DOI：
10.1111/j.1742-7843.2012.00909.x
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发表时间：
2012
影响因子：
3.1
通讯作者：
Maki Mizogami and Kenji Shigemi
中科院分区：
文献类型：
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作者：
Hironori Tsuchiya;Maki Mizogami and Kenji Shigemi
虽然心肌缺血增强了局部麻醉剂的心脏毒性，但其药理学背景仍不清楚。定位于线粒体膜上的心磷脂(CL)可能是局麻药心脏毒性作用的部位，而过氧亚硝酸盐则是由心肌缺血和再灌流产生的。我们验证了局部麻醉剂可能与含CL的生物膜相互作用从而改变膜的生物物理性质的假说机制，并且过氧亚硝酸根可能增加了它们之间的膜相互作用。用不同组成的磷脂和胆固醇制备了仿生膜。膜制剂分别与病理相关浓度的过氧亚硝酸盐和心脏毒性浓度的局部麻醉剂(布比卡因和利多卡因)反应。通过测量荧光偏振度来确定膜流动性的变化。过氧亚硝酸根降低了CL>；1‐stearoyl‐2‐arachidonoylphosphatidylcholine>；1，2‐dipalmitoylphosphatidylcholine‐constituting膜的流动性，其相对效力为μ膜，表明膜脂的不饱和度决定了膜脂过氧化诱导的膜僵硬。当用0.1-10μM过氧亚硝酸盐处理时，随着CL含量从0%增加到30%，仿生膜更加坚硬，这表明CL是过氧亚硝酸根的主要靶标。布比卡因和利多卡因在含10μ%CL的2 0 0μM仿生膜上流态化，用0.1和1 M过氧亚硝酸根预处理膜可增强其作用。心脏毒性的布比卡因和利多卡因越来越多地与含有CL的线粒体模型膜相互作用，后者被过氧亚硝酸根相对刚性。这种不断增加的膜相互作用可能至少部分是局部麻醉剂心脏毒性因心肌缺血而增强的原因。
While myocardial ischaemia enhances the cardiotoxicity of local anaesthetics, the pharmacological background remains unclear. Cardiolipin (CL) localized in mitochondrial membranes is possibly the site of cardiotoxic action of local anaesthetics and peroxynitrite is produced by cardiac ischaemia and reperfusion. We verified the hypothetic mechanism that local anaesthetics may interact with CL‐containing biomembranes to change the membrane biophysical property and their membrane interactions may be increased by peroxynitrite. Biomimetic membranes were prepared with different phospholipids and cholesterol of varying compositions. The membrane preparations were reacted with peroxynitrite of pathologically relevant concentrations and local anaesthetics (bupivacaine and lidocaine) of a cardiotoxic concentration separately or in combination. Changes in membrane fluidity were determined by measuring fluorescence polarization. Peroxynitrite decreased the fluidity of biomimetic membranes at 0.1–10 μM with the relative potency being CL>1‐stearoyl‐2‐arachidonoylphosphatidylcholine>1,2‐dipalmitoylphosphatidylcholine‐constituting membranes, indicating the lipid peroxidation‐induced membrane rigidification determined by the unsaturation degree of membrane lipids. When treated with 0.1–10 μM peroxynitrite, biomimetic membranes were more rigid with elevating the CL content from 0% to 30 mol%, suggesting that CL is a primary target of peroxynitrite. Bupivacaine and lidocaine fluidized at 200 μM biomimetic membranes containing 10 mol% CL and their effects were increased by pre‐treating the membranes with 0.1 and 1 μM peroxynitrite. Cardiotoxic bupivacaine and lidocaine increasingly interact with CL‐containing mitochondria model membranes which are relatively rigidified by peroxynitrite. Such an increasing membrane interaction may be, at least in part, responsible for the local anaesthetic cardiotoxicity enhanced by myocardial ischaemia.