Earm Y E, Ho W K, So I
Department of Physiology, Seoul National University College of Medicine, Korea.
J Mol Cell Cardiol. 1994 Feb;26(2):163-72. doi: 10.1006/jmcc.1994.1019.
Adriamycin has been widely used as an anticancer drug, but its clinical use is limited by a dose-dependent cardiac toxicity. Proposed mechanisms for the adriamycin-induced cardiomyopathy include increasing the Ca current, inhibiting the Na/Ca exchange and dysfunction of the sarcoplasmic reticulum (SR). Using the whole cell voltage clamp technique in single isolated atrial and ventricular myocytes of the rabbit, we have investigated the effect of adriamycin on various current systems which are related to regulating intracellular Ca concentration: the Ca current, the Na/Ca exchange current and [Ca2+]i-dependent currents (ouabain-induced transient inward current and the inward tail current). Adriamycin, 0.05 mg/ml, increased Ca current (L-type) by 61%. Adriamycin inhibited the inward tail current in a dose-dependent manner between 0.02 and 0.1 mg/ml and when low concentration was used the effect was reversible. Ouabain-induced transient inward current was also suppressed by 0.05 mg/ml adriamycin. Na/Ca exchange current which is partly responsible for inducing [Ca2+]i-dependent currents was, however, not affected by adriamycin, suggesting that the effect adriamycin on [Ca2+]i-dependent currents is due to inhibition of SR function. From these results it is suggested that the increase of Ca current and inhibition of SR function cause adriamycin-induced cardiac toxicity: SR dysfunction not only causes a decrease of myocardial contractility, it can also accelerate the Ca overload process which might originate from the increase of Ca current.
阿霉素已被广泛用作抗癌药物，但其临床应用受到剂量依赖性心脏毒性的限制。阿霉素诱导的心肌病的潜在机制包括增加钙电流、抑制钠/钙交换以及肌浆网（SR）功能障碍。我们使用全细胞电压钳技术，对兔单个分离的心房和心室肌细胞进行研究，以探讨阿霉素对与调节细胞内钙浓度相关的各种电流系统的影响：钙电流、钠/钙交换电流以及[Ca2+]i依赖性电流（哇巴因诱导的短暂内向电流和内向尾电流）。0.05毫克/毫升的阿霉素使钙电流（L型）增加了61%。阿霉素在0.02至0.1毫克/毫升之间以剂量依赖性方式抑制内向尾电流，且低浓度使用时该作用是可逆的。0.05毫克/毫升的阿霉素也抑制了哇巴因诱导的短暂内向电流。然而，部分负责诱导[Ca2+]i依赖性电流的钠/钙交换电流不受阿霉素影响，这表明阿霉素对[Ca2+]i依赖性电流的作用是由于抑制了肌浆网功能。从这些结果表明，钙电流的增加和肌浆网功能的抑制导致了阿霉素诱导的心脏毒性：肌浆网功能障碍不仅导致心肌收缩力下降，还可加速可能源于钙电流增加的钙超载过程。
