Role of mitochondrial dysfunction in cardiac glycoside toxicity.
Role of mitochondrial dysfunction in cardiac glycoside toxicity.
复制标题
DOI：
10.1016/j.yjmcc.2010.06.012
复制
发表时间：
2010-11
影响因子：
5
通讯作者：
O'Rourke B
中科院分区：
文献类型：
--
作者：
Liu T;Brown DA;O'Rourke B
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+]i) compromises mitochondrial energetics and redox balance by blunting mitochondrial Ca2+ ([Ca2+]m) accumulation, and this impairment can be prevented by enhancing [Ca2+]m. 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 Ca2+ efflux, via inhibition of the mitochondrial Na+/Ca2+ exchanger (mNCE). In isolated cardiomyocytes, ouabain elevated [Na+]i in a dose-dependent way, blunted [Ca2+]m 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 Ca2+ 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 heart and in vivo. The findings reveal the mechanism behind cardiac glycoside toxicity and show that improving mitochondrial Ca2+ retention by mNCE inhibition can mitigate these effects, particularly with respect to the suppression of Ca2+-triggered arrhythmias, while enhancing positive inotropic actions. These results suggest a novel strategy for the treatment of heart failure.
登录
查看更多内容
影响因子：
5.9
作者：
COVIT, AB;SCHAER, GL;CODY, RJ
通讯作者：
CODY, RJ
DOI：
10.1083/jcb.145.4.795
发表时间：
1999-05-17
期刊：
The Journal of cell biology
影响因子：
--
作者：
Boitier E;Rea R;Duchen MR
通讯作者：
Duchen MR
DOI：
10.1016/j.ddmod.2007.11.003
发表时间：
2007-01-01
期刊：
Drug discovery today. Disease models
影响因子：
--
作者：
O'Rourke, Brian;Maack, Christoph
通讯作者：
Maack, Christoph
影响因子：
10.8
作者：
CURTIS, MJ;WALKER, MJA
通讯作者：
WALKER, MJA
影响因子：
158.5
作者：
PACKER, M;GHEORGHIADE, M;JOLLY, MK
通讯作者：
JOLLY, MK