The Johns Hopkins University, Institute of Molecular Cardiobiology, Division of Cardiology, Department of Medicine, 720 Rutland Ave., 1060 Ross Bldg, Baltimore, MD 21205-2195, USA.
J Mol Cell Cardiol. 2010 Nov;49(5):728-36. doi: 10.1016/j.yjmcc.2010.06.012. Epub 2010 Jul 8.
Cardiac glycosides, which inhibit the plasma membrane Na(+) pump, are one of the four categories of drug recommended for routine use to treat heart failure, yet their therapeutic window is limited by toxic effects. Elevated cytoplasmic Na(+) (Na(+)) compromises mitochondrial energetics and redox balance by blunting mitochondrial Ca(2+) (Ca(2+)) accumulation, and this impairment can be prevented by enhancing Ca(2+). Here, we investigate whether this effect underlies the toxicity and arrhythmogenic effects of cardiac glycosides and if these effects can be prevented by suppressing mitochondrial Ca(2+) efflux, via inhibition of the mitochondrial Na(+)/Ca(2+) exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated Na(+) in a dose-dependent way, blunted Ca(2+) accumulation, decreased the NADH/NAD+redox potential, and increased reactive oxygen species (ROS). Concomitant treatment with the mNCE inhibitor CGP-37157 ameliorated these effects. CGP-37157 also attenuated ouabain-induced cellular Ca(2+) overload and prevented delayed afterdepolarizations (DADs). In isolated perfused hearts, ouabain's positive effects on contractility and respiration were markedly potentiated by CGP-37157, as were those mediated by β-adrenergic stimulation. Furthermore, CGP-37157 inhibited the arrhythmogenic effects of ouabain in both isolated perfused hearts and in vivo. The findings reveal the mechanism behind cardiac glycoside toxicity and show that improving mitochondrial Ca(2+) retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca(2+)-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure.
强心苷抑制质膜 Na+泵，是推荐用于常规治疗心力衰竭的四类药物之一，但它们的治疗窗口受到毒性作用的限制。细胞质 Na+升高 ([Na+]i) 通过削弱线粒体 Ca2+ ([Ca2+]m) 积累来损害线粒体能量代谢和氧化还原平衡，而这种损伤可以通过增强 [Ca2+]m 来预防。在这里，我们研究了这种作用是否是强心苷毒性和致心律失常作用的基础，以及通过抑制线粒体 Na+/Ca2+交换体 (mNCE) 抑制线粒体 Ca2+外流是否可以预防这些作用。在分离的心肌细胞中，哇巴因呈剂量依赖性方式升高 [Na+]i，削弱 [Ca2+]m 积累，降低 NADH/NAD+氧化还原电位，并增加活性氧物种 (ROS)。同时用 mNCE 抑制剂 CGP-37157 处理可改善这些作用。CGP-37157 还可减轻哇巴因诱导的细胞 Ca2+过载，并防止延迟后除极 (DAD)。在分离的灌流心脏中，CGP-37157 明显增强了哇巴因对收缩力和呼吸的正性作用，以及β-肾上腺素能刺激介导的作用。此外，CGP-37157 抑制了哇巴因在分离灌流心脏和体内的致心律失常作用。这些发现揭示了强心苷毒性的作用机制，并表明通过 mNCE 抑制改善线粒体 Ca2+保留可以减轻这些作用，特别是在抑制 Ca2+触发的心律失常方面，同时增强正性变力作用。这些结果为心力衰竭的治疗提供了一种新策略。
