![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication April 21, 2005.
Revised June 20, 2005.
Accepted for publication June 20, 2005.
A variety of drugs have been reported to cause acquired LQTS through inhibition of the IKr channel. Screening compounds in early discovery and development stages against their ability to inhibit IKr or the hERG channel has therefore become an indispensable procedure in the pharmaceutical industry. In contrast to numerous hERG channel blockers discovered during screening, so far only RPR260243 has been reported to enhance the hERG current. In this article, we describe several potent, mechanistically distinct hERG channel enhancers. One example is PD-118057 which produced average increases of 5.5 ± 1.1, 44.8 ± 3.1, and 111.1 ± 21.7% in the peak tail hERG current at 1, 3 and 10 µM, respectively, in HEK-293 cells. PD-118057 did not affect the voltage dependence of gating parameters, nor did it have any significant effect on activation, deactivation and recovery kinetics. In isolated guinea-pig cardiomyocytes, PD-118057 showed no major effect on INa, ICa,L, IK1 and IKs. PD-118057 shortened the action potential duration and QT interval in arterially perfused rabbit ventricular wedge preparation in a concentration-dependent manner. Presence of 3-µM PD-118057 prevented APD and QT prolongation caused by dofetilide. Early after depolarizations induced by dofetilide were also completely eliminated by 3 µM PD-118057. While further investigation is warranted to evaluate the therapeutic value and safety profile of these compounds, our data support the notion that hERG activation by pharmaceuticals may offer a new approach in the treatment of delayed repolarization conditions which may occur in inherited or acquired LQTS, CHF and diabetes patients.
Key words:
Potassium, Antiarrhythmic drugs
This article has been cited by other articles:
|
|
 |
|
  T. G. Diness, Y.-H. Yeh, X. Y. Qi, D. Chartier, Y. Tsuji, R. S. Hansen, S.-P. Olesen, M. Grunnet, and S. Nattel Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome Cardiovasc Res, July 1, 2008; 79(1): 61 - 69. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Xu, M. Recanatini, M. Roberti, and G.-N. Tseng Probing the Binding Sites and Mechanisms of Action of Two Human Ether-a-go-go-Related Gene Channel Activators, 1,3-bis-(2-Hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643) and 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic acid (PD307243) Mol. Pharmacol., June 1, 2008; 73(6): 1709 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Perry and M. C. Sanguinetti A Single Amino Acid Difference between Ether-a-go-go- Related Gene Channel Subtypes Determines Differential Sensitivity to a Small Molecule Activator Mol. Pharmacol., April 1, 2008; 73(4): 1044 - 1051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fernandez, J. Sargent, F. B. Sachse, and M. C. Sanguinetti Structural Basis for Ether-a-go-go-Related Gene K+ Channel Subtype-Dependent Activation by Niflumic Acid Mol. Pharmacol., April 1, 2008; 73(4): 1159 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Gordon, I. M. Lozinskaya, Z. Lin, S. F. Semus, F. E. Blaney, R. N. Willette, and X. Xu 2-[2-(3,4-Dichloro-phenyl)-2,3-dihydro-1H-isoindol-5-ylamino]-nicotinic Acid (PD-307243) Causes Instantaneous Current through Human Ether-a-go-go-Related Gene Potassium Channels Mol. Pharmacol., March 1, 2008; 73(3): 639 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Perry, F. B. Sachse, and M. C. Sanguinetti Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator PNAS, August 21, 2007; 104(34): 13827 - 13832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Hansen, S.-P. Olesen, and M. Grunnet Pharmacological Activation of Rapid Delayed Rectifier Potassium Current Suppresses Bradycardia-Induced Triggered Activity in the Isolated Guinea Pig Heart J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 996 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nattel, A. Maguy, S. Le Bouter, and Y.-H. Yeh Arrhythmogenic Ion-Channel Remodeling in the Heart: Heart Failure, Myocardial Infarction, and Atrial Fibrillation Physiol Rev, April 1, 2007; 87(2): 425 - 456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. M. Yeung and I. A. Greenwood Pharmacological and biophysical isolation of K+ currents encoded by ether-a-go-go-related genes in murine hepatic portal vein smooth muscle cells Am J Physiol Cell Physiol, January 1, 2007; 292(1): C468 - C476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zeng, I. M. Lozinskaya, Z. Lin, R. N. Willette, D. P. Brooks, and X. Xu Mallotoxin Is a Novel Human Ether-a-go-go-Related Gene (hERG) Potassium Channel Activator J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 957 - 962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Hansen, T. G. Diness, T. Christ, E. Wettwer, U. Ravens, S.-P. Olesen, and M. Grunnet Biophysical Characterization of the New Human Ether-A-Go-Go-Related Gene Channel Opener NS3623 [N-(4-Bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl)urea] Mol. Pharmacol., October 1, 2006; 70(4): 1319 - 1329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Casis, S.-P. Olesen, and M. C. Sanguinetti Mechanism of Action of a Novel Human ether-a-go-go-Related Gene Channel Activator Mol. Pharmacol., February 1, 2006; 69(2): 658 - 665. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
