Inhibition of T-type and L-type calcium channels by mibefradil: Physiologic and pharmacologic bases of cardiovascular effects
Inhibition of T-type and L-type calcium channels by mibefradil: Physiologic and pharmacologic bases of cardiovascular effects
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DOI：
10.1097/00005344-200106000-00002
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发表时间：
2001-06-01
影响因子：
3
通讯作者：
Richard, S
中科院分区：
文献类型：
--
作者：
Leuranguer, V;Mangoni, ME;Richard, S
二氢吡啶的钙通道拮抗剂。苯并硫氮卓类和苯基烷胺类对L型钙通道和T型钙通道有选择性作用。相比之下，米贝拉地尔被报道对T型通道更具选择性。采用全细胞膜片钳技术，观察米贝地尔对不同类型心肌细胞生理性细胞外钙电流(I-CAT和I-Cal)的影响。在0.1 Hz的刺激频率下，米贝法地尔阻断大鼠心房细胞负保持电位(-100 mV~-80 mV)诱发的I-CAT，IC50为0.1um。该浓度对大鼠心室肌细胞i-Cal无影响(IC50：与3um相似)。然而，当HP去极化到-50 mV(IC50：类似于0.1um)时，I-Cal的阻断作用增强。除静息阻滞外，mibefradil对I-cat和I-Cal均表现出电压和使用依赖性效应。此外，随着阶跃去极化持续时间的增加，抑制作用增强。在人的心房和兔的窦房结细胞上也观察到类似的作用。综上所述，米贝拉地尔结合了二氢吡啶和苯并硫氮类药物对i-Cal的电压依赖和使用依赖效应。抑制i-Cal离子可能是米贝法地尔的心血管作用的主要原因，这可能是以前被低估的。
Ca2+ channel antagonists of the dihydropyridine. benzothiazepine, and phenylalkylamine: classes have selective effects on L-type versus T-type Ca2+ channels. In contrast, mibefradil was reported to be more selective for T-type channels. We used the whole-cell patch-clamp technique to investigate the effects of mibefradil on T-type and L-type Ca2+ currents (I-CaT and I-CaL) recorded at physiologic extracellular Ca2+ in different cardiac cell types. At a stimulation rate of 0.1 Hz, mibefradil blocked I-CaT evoked from negative holding potentials (HPs) (-100 mV to -80 mV) with an IC50 of 0.1 muM in rat atrial cells. This concentration had no effect on I-CaL in rat ventricular cells (IC50: similar to3 muM). However, block of I-CaL was enhanced when the HP was depolarized to -50 mV (IC50: similar to0.1 muM). Besides a resting block, mibefradil displayed voltage- and use-dependent effects on both I-CaT and I-CaL. In addition, inhibition was enhanced by increasing the duration of the step-depolarizations. Similar effects were observed in human atrial and rabbit sinoatrial cells. In conclusion, mibefradil combines the voltage- and use-dependent effects of dihydropyridines and benzothiazepines on I-CaL. Inhibit ion of I-CaL, which has probably been underestimated before, may contribute to most of the cardiovascular effects of mibefradil.