Khodorov B I, Zaborovskaya L D
Drugs Exp Clin Res. 1986;12(9-10):743-52.
Voltage clamp studies were carried out of the effects of chloramine-T(CT) and external Ca++ on the blocking interactions of local anaesthetics (LAs) and antiarrhythmic drugs (lidocaine, tetracaine, N-propyl ajmaline, compound KC 3791) with Na+ channels in frog Ranvier nodes. The results obtained provided direct evidence for the notion that: LAs interact preferentially with inactivated Na+ channels and stabilize their inactivated conformation ("drug-induced slow inactivation": SI); and SI underlies the cumulative inhibition of INa during repetitive membrane stimulation. Normal inactivation is not indispensable, but plays an auxiliary role in the mechanism of cumulative inhibition of INa by drugs interacting with open Na+ channels. This block results mainly from accumulation of the channels in the resting blocked state (due to the inability of charged drugs to leave the channel via a "hydrophobic pathway"). The contribution of the blockade-inactivated state to this type of block may depend on some properties of the drug and the holding membrane potential. The problem of the location of the binding site responsible for LA-induced SI requires further investigation in view of the fact that in the myocardium, along with LA, the lipid-insoluble tetrodotoxin (TTX) induces a pronounced SI.
进行了电压钳研究，以探讨氯胺-T（CT）和细胞外Ca++对局部麻醉药（LAs）和抗心律失常药物（利多卡因、丁卡因、N-丙基阿马林、化合物KC 3791）与青蛙郎飞结处Na+通道阻断相互作用的影响。所得结果为以下观点提供了直接证据：局部麻醉药优先与失活的Na+通道相互作用并稳定其失活构象（“药物诱导的缓慢失活”：SI）；并且SI是重复膜刺激期间INa累积抑制的基础。正常失活并非不可或缺，但在与开放的Na+通道相互作用的药物对INa的累积抑制机制中起辅助作用。这种阻断主要是由于通道在静息阻断状态下的积累（由于带电药物无法通过“疏水途径”离开通道）。阻断失活状态对这种类型阻断的贡献可能取决于药物的某些特性和保持膜电位。鉴于在心肌中，除了局部麻醉药外，脂溶性的河豚毒素（TTX）也会诱导明显的SI，负责局部麻醉药诱导的SI的结合位点的位置问题需要进一步研究。
