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阻滞神经。局部麻醉药从细胞内环境进入钠通道。首先，我们测定了在螯虾巨大轴突中神经被阻断时利多卡因和布比卡因的细胞内浓度。灌注利多卡因或布比卡因溶液，神经阻滞被确定为强直或相位电刺激后诱发动作电位的缺乏。使用利多卡因或布比卡因敏感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，布比卡因的浓度更小，更有效，更迅速地实现了相位阻滞。观察到利多卡因的细胞内浓度比布比卡因大11至16倍，以阻滞单个神经。利多卡因的细胞内浓度与细胞外浓度的比值显著大于布比卡因。这些结果表明，布比卡因产生更有效的神经阻滞和使用依赖性（阶段性）阻滞在较小的浓度比利多卡因。其次，我们测定了利多卡因单独或二甲亚砜（DMSO）含利多卡因阻滞神经时利多卡因的细胞内浓度。DMSO呈剂量依赖性地阻断螯虾巨轴突，而0.2%DMSO不阻断。然而，含0.2% DMSO的利多卡因产生的阻滞作用明显大于单独使用利多卡因。含0. 2%DMSO的利多卡因和单独利多卡因的细胞内/细胞外比例相似。这些结果表明，除了轴浆钠通道的阻滞作用外，神经传导阻滞还受到其他机制的影响。

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.