Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX
Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX
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DOI：
10.1038/sj.bjp.0702901
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发表时间：
1999-11-01
影响因子：
7.3
通讯作者：
De Luca, A
中科院分区：
文献类型：
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作者：
Desaphy, JF;Camerino, DC;De Luca, A
1抗抑郁药美西律（Mex）也用于治疗肌强直。为了寻找更有效的药物，合成了一种新的化合物（Me 5），将Mex手性碳原子上的甲基取代为异丙基。使用细胞贴附膜片钳方法比较Me 5和Mex对大鼠骨骼肌纤维Na+通道的影响。2 Me 5（10 μ M）在0.3 Hz刺激频率下使最大钠电流（I-Na）降低29.7+/-4.4%（n = 6），在1 Hz刺激频率下降低65.7+/-4.4%（n=6）。在相同浓度（10 μ M）下，Mex不能产生任何效应（n=3）。Me 5还使稳态失活曲线在0.3 Hz下移动-7.9+/-0.9 mV（n = 6），在1 Hz下移动-12.2+/-1.0 mV（n = 6）。3在海葵毒素II（ATX; 5 μ M）存在下，I-Na衰减更慢，不再为零，提供了钠通道肌强直模型。无论ATX存在与否，Me 5对I-Na峰的影响相似。有趣的是，Me 5没有改变I-Na衰减时间常数，也没有改变稳态I-Na与峰值I-Na的比率。4 ATX诱导的晚期Na+通道活性的分析表明，Me 5没有影响平均开放时间和单通道电导，因此排除了开放通道阻断特性。5这些结果表明，增加Mex手性原子上的位阻增加了对野生型和ATX诱导的非失活I-的药物效力。Na和Me 5可能有助于预防肌强直。
1 The antiarrhythmic drug mexiletine (Mex) is also used against myotonia. Searching for a more efficient drug, a new compound (Me5) was synthesized substituting the methyl group on the chiral carbon atom of Mex by an isopropyl group. Effects of Me5 on Na+ channels were compared to those of Mex in rat skeletal muscle fibres using the cell-attached patch clamp method.2 Me5 (10 mu M) reduced the maximal sodium current (I-Na) by 29.7+/-4.4 % (n = 6) at a frequency of stimulation of 0.3 Hz and 65.7+/-4.4 % (n=6) at 1 Hz. At same concentration (10 mu M), Mex was incapable of producing any effect (n=3). Me5 also shifted the steady-state inactivation curves by -7.9+/-0.9 mV (n = 6) at 0.3 Hz and -12.2+/-1.0 mV (n = 6) at 1 Hz.3 In the presence of sea anemone toxin II (ATX; 5 mu M), I-Na decayed more slowly and no longer to zero, providing a model of sodium channel myotonia. The effects of Me5 on peak I-Na were similar whatever ATX was present or not. Interestingly, Me5 did not modify the I-Na decay time constant nor the steady-state I-Na to peak I-Na ratio.4 Analysis of ATX-induced late Na+ channel activity shows that Me5 did not affect mean open times and single-channel conductance, thus excluding open channel block property.5 These results indicate that increasing hindrance on the chiral atom of Mex increases drug potency on wild-type and ATX-induced noninactivating I-Na and that Me5 might improve the prophylaxis of myotonia.