Kim D H, Landry A B, Lee Y S, Katz A M
Department of Medicine, University of Connecticut Health Centre, Farmington 06032.
J Mol Cell Cardiol. 1989 May;21(5):433-6. doi: 10.1016/0022-2828(89)90782-7.
Doxorubicin, an anthracycline glycoside antibiotic which has been widely used for treatment of several types of cancer (Goormaghtigh and Ruysschaer, 1984), displays a clinically important cardiac toxicity (Young et al., 1981) that can be dissociated from the antitumor activity. Although the main sites of toxicity have been postulated to be on the muscle membranes (Goormaghtigh and Ruysschaer, 1984; Harris and Doroshow, 1985), no information is available for a direct doxorubicin effect on the Ca2+ fluxes in cardiac sarcoplasmic reticulum (SR). Previous studies have shown that micromolar doxorubicin triggers Ca2+ release from skeletal SR vesicles (Zorzato et al., 1985). The objective of this study was to examine the effect of doxorubicin or caffeine on Ca2+ fluxes in cardiac SR in the presence of various Ca2+ release inhibitors. Addition of either doxorubicin (C1/2 = 5 microM), or caffeine (C1/2 = 0.8 mM) triggered Ca2+ release from canine cardiac SR loaded with 45Ca2+ in the presence of 2 mM ATP. The maximal amount of Ca2+ release triggered by doxorubicin (38% of the total loaded Ca2+) was significantly higher than that released by caffeine (25%). Plots of the amount of Ca2+ release triggered by 20 microM doxorubicin or 2 mM caffeine vs. free Ca2+ concentration were a bell-shaped, with maximal Ca2+ release at 0.2 microM Ca2+. Ca2+ release triggered by either 20 microM doxorubicin or 2 mM caffeine was inhibited by ruthenium red (0.1 to 2 microM), ryanodine (1 to 100 microM) or tetracaine (0.1 to 1 mM), whereas 2 mM caffeine did not further activate Ca2+ release triggered by 50 microM doxorubicin, suggesting that the drugs may share the same Ca2+ release channel.
阿霉素是一种蒽环类糖苷抗生素，已被广泛用于治疗多种类型的癌症（古尔马希蒂和鲁伊斯沙尔，1984年），它具有临床上重要的心脏毒性（杨等人，1981年），且这种毒性可与抗肿瘤活性相分离。尽管毒性的主要部位据推测是在肌膜上（古尔马希蒂和鲁伊斯沙尔，1984年；哈里斯和多罗肖，1985年），但关于阿霉素对心肌肌浆网（SR）中Ca2+通量的直接影响尚无相关信息。先前的研究表明，微摩尔浓度的阿霉素会触发骨骼肌SR囊泡释放Ca2+（佐尔扎托等人，1985年）。本研究的目的是在存在各种Ca2+释放抑制剂的情况下，研究阿霉素或咖啡因对心肌SR中Ca2+通量的影响。在存在2 mM ATP的情况下，添加阿霉素（半数有效浓度C1/2 = 5 microM）或咖啡因（C1/2 = 0.8 mM）均可触发从加载了45Ca2+的犬心肌SR中释放Ca2+。阿霉素触发的Ca2+最大释放量（占总加载Ca2+的38%）显著高于咖啡因触发的释放量（25%）。20 microM阿霉素或2 mM咖啡因触发的Ca2+释放量与游离Ca2+浓度的关系图呈钟形，在0.2 microM Ca2+时Ca2+释放量最大。20 microM阿霉素或2 mM咖啡因触发的Ca2+释放均受到钌红（0.1至2 microM）、ryanodine（1至100 microM）或丁卡因（0.1至1 mM）的抑制，而2 mM咖啡因不会进一步激活50 microM阿霉素触发的Ca2+释放，这表明这些药物可能共用相同的Ca2+释放通道。
