hERG1 channel activators: A new anti-arrhythmic principle |
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Authors: | Morten Grunnet Rie Schultz Hansen Sren-Peter Olesen |
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Institution: | aNeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark;bDanish National Research Foundation Centre for Cardiac Arrhythmia, University of Copenhagen, Denmark |
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Abstract: | The cardiac action potential is the result of an orchestrated function of a number of different ion channels. Action potential repolarisation in humans relies on three potassium current components named IKr, IKs and IK1 with party overlapping functions. The ion channel α-subunits conducting these currents are hERG1 (Kv11.1), KCNQ1 (Kv7.1) and Kir2.1. Loss-of-function in any of these currents can result in long QT syndrome. Long QT is a pro-arrhythmic disease with increased risk of developing lethal ventricular arrhythmias such as Torsade de Pointes and ventricular fibrillation. In addition to congenital long QT, acquired long QT can also constitute a safety risk. Especially unintended inhibition of the hERG1 channel constitutes a major concern in the development of new drugs. Based on this knowledge is has been speculated whether activation of the hERG1 channel could be anti-arrhythmic and thereby constitute a new principle in treatment of cardiac arrhythmogenic disorders. The first hERG1 channel agonist was reported in 2005 and a limited number of such compounds are now available. In the present text we review results obtained by hERG1 channel activation in a number of cardiac relevant settings from in vitro to in vivo. It is demonstrated how the principle of hERG1 channel activation under certain circumstances can constitute a new anti-arrhythmogenic principle. Finally, important conceptual differences between the short QT syndrome and the hERG1 channel activation, are evaluated. |
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Keywords: | Kv11 1 Arrhythmia Pharmacological treatment Repolarisation reserve Triggered activity Fibrillation |
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