Studies of local anesthetics on use-dependent block

临床上，利多卡因需要比布比卡因更大的浓度来麻醉神经。局部麻醉剂从细胞内环境进入钠通道。首先，当小龙虾的巨大轴突中的一条神经被阻断时，我们测定了利多卡因和布比卡因的细胞内浓度。灌流利多卡因或布比卡因溶液，神经阻滞被确定为紧张性或相性电刺激后没有诱发动作电位。用对利多卡因或布比卡因敏感的玻璃微电极测量细胞内利多卡因或布比卡因浓度。与利多卡因相比，布比卡因浓度较低时，可更有效、更迅速地达到时相阻滞。利多卡因的细胞内浓度是布比卡因的11到16倍，用来阻断一条神经。利多卡因的细胞内外浓度比布比卡因大得多。这些发现表明，与利多卡因相比，布比卡因在较小的浓度下会产生更有效的神经阻滞和使用依赖(时相)阻滞。其次，我们测定了利多卡因单独或含有二甲基亚砜(DMSO)的利多卡因阻断神经时的细胞内利可卡因浓度。DMSO可剂量依赖性地阻断小龙虾的巨型轴突，但0.2%DMSO不能阻断。然而，0.2%含DMSO的利多卡因比单独使用利多卡因产生更大的阻滞。在含0.2%二甲基亚砜的利多卡因和单独使用利多卡因的细胞内和细胞外的比例相似。这些结果表明，神经传导阻滞除阻断轴浆钠通道的作用外，还存在其他机制的改变。

Clinically, lidocaine requires a large concentration than bupivacaine to block nerves. Local anesthetics access to sodium channels from the intracellular milieu. Primarily, we determined the intracellular concentrations of lidocaine and bupivacaine when a nerve was blocked in the giant axon of a crayfish. A solution of lidocaine or bupivacaine was perfused, and a nerve block was determined as the absence of an evoked action potential after tonic or phasic electrical stimulation. The intracellular lidocaine or bupivacaine concentration was measured using a lidocaine- or bupivacaine-sensitive glass microelectrode. A phasic block was more effectively and rapidly achieved with a smaller concentration of bupivacaine than with lidocaine. An 11 to 16-fold larger intracellular concentration of lidocaine than bupivacaine was observed to block a single nerve. The ratio of the intra-to extracellular concentration was significantly larger for lidocaine than for bupivacaine. These findings suggest that bupivacaine produces a more potent nerve block and a use-dependent (phasic) block at smaller concentrations than lidocaine. Secondarily, we determined the intracellular concentration of licocaine when a nerve was blocked with lidocaine alone or dimethylsulfoxide (DMSO)-containing lidocaine. The giant axon of crayfish was blocked dose-dependently with DMSO but not blocked with 0.2%DMSO. However, 0.2%DMSO-containing lidocaine produced significantly greater block than lidocaine alone. The intra- to extracellular ratio of lidocaine was similar in the 0.2%DMSO-containing lidocaine and lidocaine alone. These results demonstrate that nerve conduction block is modified by other mechanism except blocking effect of sodium channel from the axoplasma.