- 作者：Xiaoqin Liu ; xiaoqin.liu@abbott.com ; James T. Limberis ; Zhi Su ; Kathryn Houseman ; Gilbert J. Diaz ; Gary A. Gintant ; Bryan F. Cox ; Ruth L. Martin
- 关键词：hERG activator ; Electrophysiology ; Cardiac ion channel ; Sotalol ; Terfenadine ; A-935142
- 刊名：Life Sciences
- 出版年：2012
- 出版时间：20 April, 2012
- 年：2012
- 卷：90
- 期：15-16
- 页码：607-611
- 全文大小：1324 K
Aims
In a previous study we found that A-935142 enhanced hERG current in a concentration-dependent manner by facilitating activation, reducing inactivation, and slowing deactivation (Su et al., 2009). A-935142 also shortened action potential duration (APD90) in canine Purkinje fibers and guinea pig atrial tissue. This study focused on the combined effects of the prototypical hERG enhancer, A-935142 and two hERG current blockers (sotalol and terfenadine).Main methods
The whole-cell voltage clamp method with HEK 293 cells heterologously expressing the hERG channel (Kv 11.1) was used.
Key findings
A-935142 did not compete with 3H-dofetilide binding, suggesting that A-935142 does not overlap the binding site of typical hERG blockers. In whole-cell voltage clamp studies we found: 1) 60 ¦ÌM A-935142 enhanced hERG current in the presence of 150 ¦ÌM sotalol (57.5 ¡À 5.8 % ) to a similar extent as seen with A-935142 alone (55.6 ¡À 5.1 % ); 2) 150 ¦ÌM sotalol blocked hERG current in the presence of 60 ¦ÌM A-935142 (43.5 ¡À 1.5 % ) to a similar extent as that seen with sotalol alone (42.0 ¡À 3.2 % ) and 3) during co-application, hERG current enhancement was followed by current blockade. Similar results were obtained with 60 nM terfenadine combined with A-935142.
Significance
These results suggest that the hERG enhancer, A-935142 does not compete with these two known hERG blockers at their binding site within the hERG channel. This selective hERG current enhancement may be useful as a treatment for inherited or acquired LQTS (Casis et al., 2006).