Hagane K, Akera T, Berlin J R
Department of Pharmacology and Toxicology, Michigan State University, East Lansing.
J Pharmacol Exp Ther. 1988 Aug;246(2):655-61.
The clinical use of doxorubicin is frequently limited by its depressant effects on cardiac muscle, presumably resulting from alterations of Ca2+ movements. Therefore, the modification of various Ca2+ pools that contribute to cardiac contraction was assessed from developed tension observed in isolated atrial muscle preparations incubated at 31 degrees C and stimulated at 0.5 Hz. Doxorubicin (100 or 200 microM) caused a transient positive inotropic effect followed by a sustained and marked negative effect, prolonged the time to peak twitch tension and decreased the rate of relaxation. Potentiated posttest contraction was depressed to a greater extent compared with contractions observed at 0.5-Hz stimulation. After a 3-hr exposure to doxorubicin, effects of ryanodine to depress developed tension observed in preparations stimulated at 0.5 Hz were markedly smaller, indicating a reduced contribution of the ryanodine-sensitive Ca2+ pool to contractile activation. In atrial muscle preparations obtained from guinea pigs treated for 10 days with doxorubicin (total dose 5 mg/kg iv), similar results as above were observed. Moreover, a longer quiescent period was required to attain the maximal posttest contraction. These results indicate that an acute or subacute exposure to doxorubicin impairs the function of the cardiac sarcoplasmic reticulum.
阿霉素的临床应用常常因其对心肌的抑制作用而受到限制，这种抑制作用可能是由钙离子运动的改变所致。因此，通过在31℃孵育并以0.5Hz频率刺激的离体心房肌标本中观察到的张力变化，评估了参与心脏收缩的各种钙池的变化情况。阿霉素（100或200微摩尔）引起短暂的正性肌力作用，随后是持续且显著的负性作用，延长了达到峰值抽搐张力的时间，并降低了舒张速率。与0.5Hz刺激下观察到的收缩相比，增强后的后测试收缩受到的抑制程度更大。在暴露于阿霉素3小时后，在0.5Hz刺激的标本中观察到的，由兰尼碱抑制产生的张力明显变小，这表明兰尼碱敏感钙池对收缩激活的贡献减少。在用阿霉素（静脉注射总剂量5mg/kg）治疗10天的豚鼠获得的心房肌标本中，观察到了与上述相似的结果。此外，达到最大后测试收缩需要更长的静息期。这些结果表明，急性或亚急性暴露于阿霉素会损害心脏肌浆网的功能。
