Mibefradil potently blocks ATP-activated K(+) channels in adrenal cells.
Mibefradil potently blocks ATP-activated K(+) channels in adrenal cells.
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DOI：
10.1124/mol.56.6.1192
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发表时间：
1999-12
影响因子：
3.6
通讯作者：
J. Gomora;J. A. Enyeart;J. J. Enyeart-J.
中科院分区：
文献类型：
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作者：
J. Gomora;J. A. Enyeart;J. J. Enyeart-J.
米贝拉地尔是一种新型的钙通道拮抗剂，在许多细胞中优先阻断T型钙通道。采用全细胞和单通道膜片钳记录，我们发现米贝地尔也能有效地阻断肾上腺束带细胞表达的ATP激活的K(+)通道(I(AC))。米贝法地尔可抑制I(AC)通道，其IC(50)为0.50微米，比同样条件下抑制T型钙通道的浓度低2倍。米贝地尔对I(AC)的抑制作用不依赖于膜电位。米贝拉地尔也可逆性地阻断了记录在外向外膜片上的单位I(AC)电流，具有类似的效力。停留时间直方图的分析表明，存在两种闭合状态和一种开放状态。米贝拉地尔(1微米)使两个关闭时间常数(tau(C1)和tau(C2))的持续时间分别从2.30+/-0.18和27.9+/-4.7ms增加到4.32+/-0.61和62.5+/-13.8ms，但不改变开放时间常数(tau(O))。米贝拉地尔也未能减小单位I(AC)电流的大小。米贝拉地尔也能抑制电压门控的A型K(+)电流，其浓度约为阻断I(AC)所需浓度的10倍(IC(50)=4.65微米)。这些结果证实米贝拉地尔是肾上腺束状带细胞上ATP激活的K(+)通道的有效抑制剂。它似乎通过稳定这些通道的关闭状态来发挥作用。与其选择性阻断T型钙通道相反，米贝法地尔可能是一种有效但选择性较低的K(+)通道阻滞剂。在这一点上，K(+)通道的阻断可能会产生一些与米贝拉地尔在心血管药理学中相关的毒性。
Mibefradil is a novel Ca(2+) channel antagonist that preferentially blocks T-type Ca(2+) channels in many cells. Using whole-cell and single-channel patch-clamp recording, we found that mibefradil also potently blocked an ATP-activated K(+) channel (I(AC)) expressed by adrenal zona fasciculata cells. I(AC) channels were inhibited by mibefradil with an IC(50) value of 0.50 microM, a concentration 2-fold lower than that required to inhibit T-type Ca(2+) channels under similar conditions in the same cells. The inhibition of I(AC) by mibefradil was independent of the membrane potential. Mibefradil also reversibly blocked, with similar potency, unitary I(AC) currents recorded in outside-out membrane patches. An analysis of dwell time histograms indicated the presence of two closed and one open state. Mibefradil (1 microM) increased the duration of the two closed time constants (tau(c1) and tau(c2)) from 2.30 +/- 0.18 and 27.9 +/- 4.7 ms to 4.32 +/- 0.61 and 62.5 +/- 13.8 ms, respectively, but did not alter the open time constant (tau(o)). Mibefradil also failed to reduce the size of the unitary I(AC) current. A voltage-gated A-type K(+) current was also inhibited by mibefradil at concentrations approximately 10-fold higher than those required to block I(AC) (IC(50) = 4.65 microM). These results identify mibefradil as a potent inhibitor of ATP-activated K(+) channels in adrenal zona fasciculata cells. It appears to function by stabilizing closed states of these channels. In contrast to its selective block of T-type Ca(2+) channels, mibefradil may be a potent but less-selective K(+) channel blocker. In this regard, the block of K(+) channels may produce some of the toxicity associated with mibefradil in cardiovascular pharmacology.