Mibefradil block of cloned T-type calcium channels.
Mibefradil block of cloned T-type calcium channels.
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发表时间：
2000-10
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通讯作者：
Ruth L. Martin;Jung-Ha Lee;L. Cribbs;E. Perez-Reyes;D. A. Hanck
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作者：
Ruth L. Martin;Jung-Ha Lee;L. Cribbs;E. Perez-Reyes;D. A. Hanck
米贝地尔是一种四氢萘酚衍生物，在化学结构上不同于其他钙通道拮抗剂。它是一种非常有效的抗高血压药物，据认为其作用机制是对低电压激活（T）钙通道的亲和力高于对高电压激活（L）钙通道。以钡离子（Ba²⁺）作为电荷载体来估算亲和力，预测米贝地尔对T通道的亲和力比对L通道高10到15倍。然而，据报道T通道的半数抑制浓度（IC₅₀）值约为1微摩尔，这比临床疗效所预期的值要高得多，因为该药物的相关血药浓度约为50纳摩尔。我们比较了米贝地尔对新克隆的T通道亚型α₁G、α₁H和α₁I以及一个L通道α₁C的亲和力。在10毫摩尔钡离子（Ba²⁺）条件下，米贝地尔在微摩尔范围内产生阻断作用，对T通道的亲和力比对L通道高12到13倍（约1微摩尔对13微摩尔）。当以2毫摩尔钙离子（Ca²⁺）作为电荷载体时，该药物的效果更佳；α₁G的IC₅₀降至270纳摩尔，α₁H的IC₅₀降至140纳摩尔，其亲和力比在10毫摩尔钡离子条件下分别高4.5倍和9倍。这些数据与米贝地尔在通道上的结合位点与通透离子竞争且钡离子（Ba²⁺）比钙离子（Ca²⁺）是更有效的竞争者这一观点相符。将温度升高到35℃会降低亲和力（IC₅₀为792纳摩尔）。将通道可利用性降低一半会增加亲和力（约70纳摩尔）。米贝地尔的这种亲和力特性使得这些通道很有可能是这种抗高血压药物的生理靶点。
Mibefradil is a tetralol derivative chemically distinct from other calcium channel antagonists. It is a very effective antihypertensive agent that is thought to achieve its action via a higher affinity block for low-voltage-activated (T) than for high-voltage-activated (L) calcium channels. Estimates of affinity using Ba(2+) as the charge carrier have predicted a 10- to 15-fold preference of mibefradil for T channels over L channels. However, T channel IC(50) values are reported to be approximately 1 microM, which is much higher than expected for clinical efficacy because relevant blood levels of this drug are approximately 50 nM. We compared the affinity for mibefradil of the newly cloned T channel isoforms, alpha1G, alpha1H, and alpha1I with an L channel, alpha1C. In 10 mM Ba(2+), mibefradil blocked in the micromolar range and with 12- to 13-fold greater affinity for T channels than for L channels (approximately 1 microM versus 13 microM). When 2 mM Ca(2+) was used as the charge carrier, the drug was more efficacious; the IC(50) for alpha1G shifted to 270 nM and for alpha1H shifted to 140 nM, 4.5- and 9-fold higher affinity than in 10 mM Ba. The data are consistent with the idea that mibefradil competes for its binding site on the channel with the permeant species and that Ba(2+) is a more effective competitor than Ca(2+). Raising temperature to 35 degrees C reduced affinity (IC(50) 792 nM). Reducing channel availability to half increased affinity ( approximately 70 nM). This profile of mibefradil affinity makes these channels good candidates for the physiological target of this antihypertensive agent.