Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs.
Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs.
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发表时间：
1991-11
影响因子：
3.6
通讯作者：
David S. Ragsdale;T. Scheuer;W. Catterall
中科院分区：
文献类型：
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作者：
David S. Ragsdale;T. Scheuer;W. Catterall
本研究采用全细胞电压钳记录技术，研究了苯妥英钠、卡马西平、利多卡因和维拉帕米对哺乳动物细胞中功能性表达的大鼠脑IIA型Na+通道的作用。药物阻断Na+电流的紧张和使用依赖性的方式。紧张性阻滞在去极化保持电位下更明显，在超极化膜电位下减少，反映了膜电位和稳态失活之间关系的整体负移。与苯妥英钠的剂量-反应关系支持了这一假设，即紧张性阻滞的电压依赖性是由于药物对失活通道的亲和力高于静息通道。在-62 mV时，约50%的Na+通道被13 μ M的苯妥英阻断，而治疗性脑水平为4-8 μ M。使用依赖性阻滞成分在2 Hz的40 ms长的刺激脉冲序列（从-85 mV到0 mV）中逐渐发展。在2 Hz时，维拉帕米是最有效的使用依赖性阻滞剂，利多卡因和苯妥英具有中等效力，卡马西平的效力最低。使用依赖性阻滞是由于去极化脉冲期间药物与开放和失活通道结合以及脉冲间期药物结合通道的缓慢再引发所致。维拉帕米、利多卡因和苯妥英钠都优先与开放通道结合，但维拉帕米的开放通道阻滞最为显著。在超极化膜电位下，由于药物结合通道的再引发更快，因此药物依赖性阻滞不太明显。结果表明，在哺乳动物细胞系中表达的IIA型Na+通道保留了天然Na+通道的复杂药理学特性。这些通道可能是苯妥英钠和卡马西平抗惊厥作用的重要部位。利多卡因和维拉帕米是对外周Na+和Ca 2+通道具有良好表征作用的药物，也是这些脑Na+通道的有效阻断剂。
This study examined the actions of phenytoin, carbamazepine, lidocaine, and verapamil on rat brain type IIA Na+ channels functionally expressed in mammalian cells, using the whole-cell voltage-clamp recording technique. The drugs blocked Na+ currents in both a tonic and use-dependent manner. Tonic block was more pronounced at depolarized holding potentials and reduced at hyperpolarized membrane potentials, reflecting an overall negative shift in the relationship between membrane potential and steady state inactivation. Dose-response relationships with phenytoin supported the hypothesis that the voltage dependence of tonic block resulted from the higher affinity of the drugs for inactivated than for resting channels. At -62 mV, approximately 50% of the Na+ channels were blocked by phenytoin at 13 microM, compared with therapeutic brain levels of 4-8 microM. The use-dependent component of block developed progressively during a 2-Hz train of 40-msec-long stimulus pulses from -85 mV to 0 mV. At 2 Hz, verapamil was the most potent use-dependent blocker, lidocaine and phenytoin had intermediate potencies, and carbamazepine was least effective. The use-dependent block resulted from drug binding to open and inactivated channels during the depolarizing pulses and the slow repriming of drug-bound channels during the interpulse intervals. Verapamil, lidocaine, and phenytoin all bound preferentially to open channels, but this open channel block was most striking for verapamil. Use-dependent block was less pronounced at hyperpolarized membrane potentials, due to more rapid repriming of drug-bound channels. The results indicate that type IIA Na+ channels expressed in a mammalian cell line retain the complex pharmacological properties characteristic of native Na+ channels. These channels are likely to be an important site of the anticonvulsant action of phenytoin and carbamazepine. Lidocaine and verapamil, drugs with well characterized effects on peripheral Na+ and Ca2+ channels, are also effective blockers of these brain Na+ channels.