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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels
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Heart failure drug digitoxin induces calcium uptake into cells by forming transmembrane calcium channels

机译：心力衰竭药物洋地黄毒蛋白通过形成跨膜钙通道诱导钙摄入细胞

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摘要

Digitoxin and other cardiac glycosides are important, centuries-old drugs for treating congestive heart failure. However, the mechanism of action of these compounds is still being elucidated. Calcium is known to potentiate the toxicity of these drugs, and we have hypothesized that digitoxin might mediate calcium entry into cells. We report here that digitoxin molecules mediate calcium entry into intact cells. Multimers of digitoxin molecules also are able to form calcium channels in pure planar phospholipid bilayers. These digitoxin channels are blocked by Al~(3+) and La~(3+) but not by Mg~(2+) or the classical L-type calcium channel blocker, nitrendipine. In bilayers, we find that the chemistry of the lipid affects the kinetics of the digitoxin channel activity, but not the cation selectivity. Antibodies against digitoxin promptly neutralize digitoxin channels in both cells and bilayers. We propose that these digitoxin calcium channels may be part of the mechanism by which digitoxin and other active cardiac glycosides, such as digoxin, exert system-wide actions at and above the therapeutic concentration range.
机译：Digitoxin和其他强心苷是治疗充血性心力衰竭的重要药物，已有数百年历史。但是，这些化合物的作用机理仍在阐明中。已知钙会增强这些药物的毒性，我们已经假设洋地黄毒苷可能介导钙进入细胞。我们在这里报告洋地黄毒菌分子介导钙进入完整细胞。洋地黄毒苷分子的多聚体也能够在纯平面磷脂双层中形成钙通道。这些洋地黄毒素通道被Al〜（3+）和La〜（3+）阻滞，但未被Mg〜（2+）或经典的L型钙通道阻滞剂尼群地平阻滞。在双层中，我们发现脂质的化学性质会影响洋地黄毒苷通道活性的动力学，但不会影响阳离子选择性。针对洋地黄毒的抗体迅速中和了细胞和双层中的洋地黄毒通道。我们认为这些洋地黄毒生物钙通道可能是洋地黄毒生物和其他活性强心苷（例如地高辛）在治疗浓度范围或更高浓度范围内发挥全系统作用的机制的一部分。

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