hERG1 channel activators: a new anti-arrhythmic principle.
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 I(Kr), I(Ks) and I(K1) with party overlapping functions. The ion channel alpha-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.
NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. mgr@neurosearch.dk <mgr@neurosearch.dk>
Morten
M
Grunnet
Rie Schultz
RS
Hansen
Søren-Peter
SP
Olesen
D000200:Action Potentials; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D055592:Biophysical Phenomena; D051638:Ether-A-Go-Go Potassium Channels / Q000819:agonists*; D006801:Humans; D015640:Ion Channel Gating; D054086:KATP Channels / Q000819:agonists
D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D054086:KATP Channels; C496884:KCNH1 protein, human