Studies of local anesthetics on use-dependent block

临床上，利多卡因比布比卡因需要更大的浓度才能阻断神经。局部麻醉剂从细胞内环境进入钠通道。首先，当小龙虾巨大轴突中的神经被阻断时，我们测定了细胞内利多卡因和布比卡因的浓度。灌注利多卡因或布比卡因溶液，神经阻滞被确定为在强直性或相性电刺激后没有诱发动作电位。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。较小浓度的布比卡因比利多卡因更有效、更迅速地实现相阻滞。观察到细胞内利多卡因浓度比布比卡因高11至16倍，可阻断单个神经。利多卡因细胞内与细胞外浓度之比明显大于布比卡因。这些发现表明，与利多卡因相比，布比卡因在较小浓度下产生更有效的神经阻滞和使用依赖性（阶段性）阻滞。其次，我们测定了当单独使用利多卡因或含二甲基亚砜（DMSO）的利多卡因阻断神经时，细胞内利多卡因的浓度。DMSO对小龙虾巨轴突有剂量依赖性阻断作用，0.2%DMSO对小龙虾巨轴突无阻断作用。然而，含0.2% dmso的利多卡因比单独使用利多卡因产生更大的阻滞。含0.2%二甲基亚砜的利多卡因与单独的利多卡因细胞内与细胞外的比值相似。这些结果表明，神经传导阻滞除了受到轴浆钠通道的阻断作用外，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.