Competition between lidocaine and one of its metabolites, glycylxylidide, for cardiac sodium channels.
Competition between lidocaine and one of its metabolites, glycylxylidide, for cardiac sodium channels.
复制标题
利多卡因及其代谢物之一甘氨酰二甲苯之间对心脏钠通道的竞争。
DOI：
10.1161/01.cir.78.3.692
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发表时间：
1988
期刊：
影响因子：
37.8
通讯作者：
Hondeghem,LM
中科院分区：
文献类型：
--
作者：
Bennett,PB;Woosley,RL;Hondeghem,LM
调节型受体假说认为，钠通道对抗心律失常药物有一种特殊的受体。因此，两种通过与该受体结合来阻断钠通道的药物有望争夺占有率。乙二醛(Gx)是利多卡因的脱乙基代谢物，在接受利多卡因治疗的患者体内积聚。在单个电压钳制的心肌细胞中，GX和利多卡因一样，以一种使用依赖的方式阻断心脏钠通道。但其恢复动力学与利多卡因明显不同：在-80~-100 mV时，Gx阻断的通道比利多卡因阻断的通道恢复得更快、更彻底，但在更负的电压下(-120~-140 mV)恢复得更慢。如果利多卡因和GX争夺一个共同的受体，那么在某些情况下，将“较快”的药物添加到“较慢的”药物中，会产生比单独使用较慢的药物更少的阻断。在-120 mV和-140 mV之间的电压范围内，在利多卡因中加入较慢的药物Gx总是增加阻断水平，但在9个实验中有4个实验中加入利多卡因降低了阻断水平，在9个实验中有3个实验中没有增加阻断水平。相反，在-80 mV到-100 mV的电压范围内，在Gx中加入利多卡因(较慢的药物)总是增加阻断，而在16个实验中有5个实验中Gx降低了阻断水平，而在16个实验中有7个实验中没有增加。因此，在加入更多阻滞剂后，36%的病例钠电流增加，76%的病例钠电流没有下降。这些结果可以用两种药物竞争同一受体的调制受体假说来解释。
The modulated receptor hypothesis states that sodium channels have a specific receptor for antiarrhythmic drugs. Therefore, two agents that block sodium channels by binding to this receptor are expected to compete for occupancy. Glycylxylidide (GX) is a deethylated metabolite of lidocaine that accumulates in patients on lidocaine therapy. In single, voltage-clamped cardiocytes, GX, like lidocaine, blocked cardiac sodium channels in a use-dependent manner. However, its kinetics of recovery from block were markedly different from lidocaine: at potentials between -80 and -100 mV, GX-blocked channels recovered faster and more completely than lidocaine-blocked channels but recovered more slowly at more negative potentials (-120 to -140 mV). If lidocaine and GX compete for a common receptor, then there are conditions in which addition of a "faster" drug to a "slower" drug will produce less block than the slower drug alone. At potentials between -120 and -140 mV, addition of GX (slower drug) to lidocaine always increased the level of block, but addition of lidocaine to GX decreased the block in four of nine experiments and did not increase it in three of nine experiments. Conversely, at potentials between -80 and -100 mV, addition of lidocaine (slower drug) to GX always increased block, whereas addition of GX to lidocaine reduced the level of block in five of 16 experiments and did not increase it in seven of 16 experiments. Thus, upon addition of more blocker, the sodium current increased in 36% of cases or did not decline in 76% of cases. These results can be explained by the modulated receptor hypothesis with two drugs competing for the same receptor.(ABSTRACT TRUNCATED AT 250 WORDS)