Safety Pharmacology, Department of Toxicology and Pathology, Non-Clinical Safety, Hoffmann-La Roche, Inc, Nutley, NJ 07110, USA.
Toxicol In Vitro. 2010 Apr;24(3):960-72. doi: 10.1016/j.tiv.2009.12.027. Epub 2010 Jan 11.
Altered intracellular calcium (Ca(i)(2+)) handling by cardiomyocytes has been implicated in drug-induced cardiomyopathy and arrhythmogenesis. To explore whether such alterations predict cardiotoxicity, Ca(i)(2+) imaging was conducted in cultured, spontaneously contracting Guinea pig cardiomyocytes to characterize the effects of 13 cardiotoxicants and 2 safe drugs. All cardiotoxicants perturbed Ca(i)(2+) at therapeutically relevant concentrations. The cytotoxic chemotherapeutics doxorubicin and epirubicin, known to cause cardiomyopathy, preferentially reduced Ca(i)(2+) transient amplitude and sarcoplasmic reticulum (SR) Ca(2+) content, whereas Torsade de Pointes (TdP) inducers and potent hERG channel blockers (amiodarone, cisapride, dofetilide, E-4031 and terfenadine) predominately suppressed diastolic Ca(i)(2+) and contraction rate, and prolonged Ca(i)(2+) transient duration. The molecularly targeted cancer therapeutics, sunitinib and imatinib, exhibited profound effects on Ca(i)(2+), combining effects of cytotoxic chemotherapeutics, TdP inducers and potent hERG channel blockers. TdP inducers lacking direct hERG inhibition, ouabain and pentamidine, significantly elevated Ca(i)(2+) transient amplitude and SR Ca(2+) content while aconitine primarily accelerated automaticity and elevated diastolic Ca(i)(2+) similar to ouabain. Finally, amoxicillin and aspirin did not exert any significant effects on Ca(i)(2+) at concentrations up to 100 microM. These results suggest that detecting altered Ca(i)(2+) handling in cultured cardiomyocytes may be used as an in vitro model for early cardiac drug safety assessment.
心肌细胞细胞内钙（Ca(i)(2+)）处理的改变与药物诱导性心肌病和心律失常发生有关。为了探讨这种改变是否预示着心脏毒性，我们对培养的、自发收缩的豚鼠心肌细胞进行了 Ca(i)(2+)成像，以表征 13 种心脏毒性药物和 2 种安全药物的作用。所有心脏毒性药物在治疗相关浓度下都会扰乱 Ca(i)(2+)。已知会导致心肌病的细胞毒性化疗药物多柔比星和表柔比星，优先降低 Ca(i)(2+)瞬变幅度和肌浆网（SR）Ca(2+)含量，而尖端扭转型室性心动过速（TdP）诱导剂和强效 hERG 通道阻滞剂（胺碘酮、西沙必利、多非利特、E-4031 和特非那定）主要抑制舒张期 Ca(i)(2+)和收缩率，并延长 Ca(i)(2+)瞬变持续时间。分子靶向癌症治疗药物舒尼替尼和伊马替尼对 Ca(i)(2+)表现出显著影响，兼具细胞毒性化疗药物、TdP 诱导剂和强效 hERG 通道阻滞剂的作用。缺乏直接 hERG 抑制作用的 TdP 诱导剂，哇巴因和戊烷脒，显著增加 Ca(i)(2+)瞬变幅度和 SR Ca(2+)含量，而乌头碱主要通过加速自动性和升高与哇巴因相似的舒张期 Ca(i)(2+)来发挥作用。最后，阿莫西林和阿司匹林在高达 100 microM 的浓度下对 Ca(i)(2+)没有任何显著影响。这些结果表明，在培养的心肌细胞中检测到 Ca(i)(2+)处理的改变可能被用作早期心脏药物安全性评估的体外模型。
