The pH-dependent rate of action of local anesthetics on the node of Ranvier.
The pH-dependent rate of action of local anesthetics on the node of Ranvier.
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DOI：
10.1085/jgp.69.4.475
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发表时间：
1977-04
影响因子：
3.8
通讯作者：
Hille, B
中科院分区：
文献类型：
--
作者：
Hille, B
将局部麻醉溶液突然施加到单个有髓神经纤维的外部，以测量钠通道阻滞发展的时间过程。钠电流在电压钳下测量，在溶液更换期间每秒施加几次测试脉冲。通过使用不同脂溶性和不同电荷类型的药物来研究阻断速率，并且外部pH从pH 8.3变化到pH 6以改变胺化合物的电离度。在pH 8.3时，胺麻醉剂如利多卡因、普鲁卡因、丁卡因等的半衰期总是小于2 s，通常小于1 s。将pH值降低至6.0会降低这些药物的表观效力并减缓其作用速率。中性苯并咪唑的作用速度快（1 s），不依赖于pH。阳离子季铵盐QX-572的作用速率缓慢（大于200 s），并且不依赖于pH。其他季铵麻醉剂衍生物在体外应用时无作用。结果是中性药物形式比带电药物更快地起作用，这表明外部应用的局部麻醉剂必须穿过疏水屏障才能到达它们的受体。代表药物扩散到神经纤维中的模型给出了合理的作用时间过程和合理的膜渗透系数，假设疏水屏障是节膜。参数给出，可能有必要重新解释的麻醉受体的位置上的许多已发表的实验，并在其上的药物的电荷形式是积极的，以考虑到未搅拌层，高膜渗透性和高脂溶性的影响。
Local anesthetic solutions were applied suddenly to the outside of single myelinated nerve fibers to measure the time course of development of block of sodium channels. Sodium currents were measured under voltage clamp with test pulses applied several times per second during the solution change. The rate of block was studied by using drugs of different lipid solubility and of different charge type, and the external pH was varied from pH 8.3 to pH 6 to change the degree of ionization of the amine compounds. At pH 8.3 the half-time of action of amine anesthetics such as lidocaine, procaine, tetracaine, and others was always less than 2 s and usually less than 1 s. Lowering the pH to 6.0 decreased the apparent potency and slowed the rate of action of these drugs. The rate of action of neutral benzocaine was fast (1 s) and pH independent. The rate of action of cationic quaternary QX-572 was slow (greater than 200 s) and also pH independent. Other quaternary anesthetic derivatives showed no action when applied outside. The result is that neutral drug forms act much more rapidly than charged ones, suggesting that externally applied local anesthetics must cross a hydrophobic barrier to reach their receptor. A model representing diffusion of drug into the nerve fiber gives reasonable time courses of action and reasonable membrane permeability coefficients on the assumption that the hydrophobic barrier is the nodal membrane. Arguments are given that there may be a need for reinterpretation of many published experiments on the location of the anesthetic receptor and on which charge form of the drug is active to take into account the effects of unstirred layers, high membrane permeability, and high lipid solubility.