Adriamycin Cardiotoxicity: possible pathogenic mechanisms.
Adriamycin Cardiotoxicity: possible pathogenic mechanisms.
复制标题
阿霉素心脏毒性：可能的致病机制。
DOI：
10.1016/0022-2828(81)90281-9
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发表时间：
1981
影响因子：
5
通讯作者：
Yamamura,Y
中科院分区：
文献类型：
--
作者：
Azuma,J;Sperelakis,N;Hasegawa,H;Tanimoto,T;Vogel,S;Ogura,K;Awata,N;Sawamura,A;Harada,H;Ishiyama,T;Morita,Y;Yamamura,Y
抗肿瘤药物阿霉素可引起人体心肌病，并伴有组织钙离子升高.因此，阿霉素的能力进行了测试，以影响心室细胞慢通道介导的钙离子内流的离体灌流鸡心脏。快速Na+通道被河豚毒素阻断或电压升高（25 m m）K+灭活，从而使心脏不可兴奋。低浓度的阿霉素（0.01 ~ 0.05 mg/ml）恢复了慢动作电位（AP）形式的兴奋性，并增强了异丙肾上腺素（10− 6 m）诱导的慢AP的最大上行速度（+ V ~ max）。较高浓度（0.1至0.5 mg/ml）不会诱导慢AP，实际上会抑制或阻断异丙肾上腺素诱导的慢AP。在正常台氏液灌注心脏记录的收缩中，阿霉素也有双重作用：在低浓度下，它具有正性肌力作用，而在较高浓度下，它具有负性肌力作用。阿霉素（0.05 mg/ml）使cAMP水平在15 min内增加约50%，提示这可能是其正性肌力作用的原因。较高浓度（0.3 mg/ml）也提高了环AMP，但ATP水平被抑制。在离体线粒体中，阿霉素（0.5 mg/ml）抑制ADP刺激的呼吸，这表明线粒体功能受损可能导致ATP水平降低。结果表明，低浓度的阿霉素增加慢电流，可能是通过增加环AMP水平，而高浓度（0.5毫克/毫升）抑制慢电流，可能是由于降低ATP水平。增强的Ca 2+内流（通过刺激慢通道）可能是与阿霉素诱导的心肌病相关的Ca 2+超载的一个因素。
The antitumor agent, adriamycin, causes in humans a cardiomyopathy associated with elevated tissue Ca 2+. Hence, adriamycin was tested for an ability to affect the Ca 2+ influx mediated by the slow channels in ventricular cells of isolated perfused chick hearts. The fast Na+ channels were blocked by tetrodotoxin or voltage inactivated by elevated (25 m m) K+, thus rendering the hearts inexcitable. Low concentrations of adriamycin (0.01 to 0.05 mg/ml) restored excitability in the form of slow action potentials (APs), and enhanced the maximum upstroke velocity (+ V ̇ max) of slow APs induced by isoproterenol (10− 6 m). Higher concentrations (0.1 to 0.5 mg/ml) did not induce slow APs, and actually depressed or blocked the isoproterenol-induced slow APs. On the contractions recorded from hearts perfused with normal Tyrode solution, adriamycin also had a dual effect: at low concentrations, it had a positive inotropic action, whereas at higher concentrations, it had a negative inotropic action. Adriamycin (0.05 mg/ml) caused the cyclic AMP level to increase by about 50% over the control within 15 min, thus suggesting that this might be responsible for its positive inotropism. Higher concentrations (0.3 mg/ml) also raised the cyclic AMP, but the ATP level was depressed. In isolated mitochondria, adriamycin (0.5 mg/ml) depressed ADP-stimulated respiration, suggesting that impaired mitochondrial function could cause the depressed ATP levels. The results indicate that low concentrations of adriamycin augment the slow current, possibly by an increase in cyclic AMP level, whereas high concentration (0.5 mg/ml) depresses the slow current, perhaps due to lowered ATP levels. The enhanced Ca 2+ influx (via stimulation of the slow channels) could be a factor in the Ca 2+ overload associated with the adriamycin-induced cardiomyopathy.