Voltage- and use-dependent modulation of calcium channel current in guinea pig ventricular cells by amiodarone and des-oxo-amiodarone.
Voltage- and use-dependent modulation of calcium channel current in guinea pig ventricular cells by amiodarone and des-oxo-amiodarone.
复制标题
胺碘酮和脱氧胺碘酮对豚鼠心室细胞钙通道电流的电压和使用依赖性调节。
DOI：
10.1097/00005344-199106000-00006
复制
发表时间：
1991
影响因子：
3
通讯作者：
Bennett,PB
中科院分区：
文献类型：
--
作者：
Valenzuela,C;Bennett,PB
胺碘酮是一种有效的抗心律失常药物，副作用严重。其抗心律失常作用的机制尚不清楚，但推测涉及抑制流经离子通道的电流。去氧代胺碘酮是胺碘酮的一种紧密结构类似物，它的合成是基于这样的假设，即毒性和治疗性质存在于分子的不同部分，并且化学修饰可以得到毒性较小的药物，但仍保持了胺碘酮的抗心律失常效果。采用全细胞膜片钳技术，比较了胺碘酮和去氧胺碘酮对酶分散的豚鼠心室肌细胞钙电流的影响。胺碘酮引起强直性和相性熔丝依赖性钙电流的降低。胺碘酮使膜电位与去极化时开放通道的有效性的关系(失活曲线)向更负的膜电位方向移动([Delta]-10.6$2.2 mV，n=7)。钙电流的使用依赖性降低也依赖于电压钳阶跃的频率(0.5赫兹，40.2美元7.9%；1.0赫兹，50.0美元6.7%)。右氧胺碘酮对钙电流有双重作用：在负膜电位(-45 mV)下维持膜电位数秒后，去氧胺碘酮可使钙电流增加。去氧代胺碘酮还使钙通道失活曲线向更负的膜电位方向移动，最高可达16 mV。因此，钙电流可以根据实验条件的不同而增加或减少。去氧代胺碘酮对钙电流的增强作用是短暂的，在-5min后完全被药物的拮抗作用所取代。去氧代胺碘酮对钙电流的拮抗作用也具有剂量和频率依赖性。
Amiodarone is an effective antiarrhythmic drug handicapped by serious side effects. The mechanism of its antiarrhythmic activity is not known but is presumed to involve inhibition of current flowing through ion channels. Des-oxo-amiodarone, a close structural analogue of amiodarone, was synthesized based on the hypothesis that the toxic and therapeutic properties reside in different parts of the molecule and that chemical modification could result in a less toxic agent that yet preserved amiodarone's antiarrhythmic efficacy. We compared the effects of amiodarone and des-oxo-amiodarone on Ca current in enzymatically dispersed guinea pig ventricular myocytes using the whole-cell patch-clamp method. Amiodarone caused both a tonic and a phasic fuse-dependent) reduction of the Ca current. The relationship between membrane potential and the availability for channel opening upon depolarization (inactivation curve) was shifted toward more negative membrane potentials by amiodarone ([DELTA]-10.6$$2.2 mV, n= 7). The use-dependent reduction of the Ca current was also dependent on the frequency of the voltage clamp steps (0.5 Hz, 40.2$$7.9%; 1.0 Hz, 50.0$$6.7%). Dexoxo-amiodarone had a dual effect on the Ca current: After maintaining the membrane potential for several seconds at negative membrane potentials (<-45 mV), the Ca current was increased by des-oxo-amiodarone. Des-oxo-amiodarone also shifted the Ca channel inactivation curve to more negative membrane potentials up to 16 mV. Consequently, Ca current could be increased or decreased depending on the experimental conditions. Enhancement of Ca current by des-oxo-amiodarone was transient and was supplanted entirely by the antagonistic effects of the drug after-5 min. The antagonistic effects of des-oxo-amiodarone on Ca current were also use-and frequency-dependent.