PT  - JOURNAL ARTICLE
AU  - Wang, Lu
AU  - Wible, Barbara A.
AU  - Wan, Xiaoping
AU  - Ficker, Eckhard
TI  - Cardiac Glycosides as Novel Inhibitors of Human <em>Ether-a-go-go</em>-Related Gene Channel Trafficking
AID  - 10.1124/jpet.106.113043
DP  - 2007 Feb 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 525--534
VI  - 320
IP  - 2
4099  - http://jpet.aspetjournals.org/content/320/2/525.short
4100  - http://jpet.aspetjournals.org/content/320/2/525.full
SO  - J Pharmacol Exp Ther2007 Feb 01; 320
AB  - Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na+/K+ pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K+ current (IKr) currents by approximately 50%, whereas three other cardiac membrane currents—inward rectifier current, slowly activating delayed rectifier K+ current, and calcium current—were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/IKr channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin. The American Society for Pharmacology and Experimental Therapeutics