Is cardiac IKs a relevant drug target?

See article by Nakashima et al. (pages 705–714) in this issue. It is with pleasure that I write a commentary on a new work from Stanley Nattel's laboratory. Nakashima et al. (Cardiovascular Research, this issue) have examined the actions of a relatively selective IKs blocker on a variety of cardiac electrophysiological variables in anesthetized dogs. There is an important underlying question driving this work, namely: to what extent does IKs represent a potential target for modulation of cardiac rhythm by drugs? Modulation, it should be noted, encompasses pro-arrhythmic as well as antiarrhythmic actions. Since the first full characterization of IKs as a component of the composite current, IK, it has been clear that drugs differ in their selectivity for IKs versus its cohabitee in repolarization, IKr[1]. The number of relatively selective IKr blockers developed over the years as antiarrhythmics far outweighs the number of relatively selective IKs blockers, owing in part to the use of d-sotalol as the prototype containing the presumed pharmacophore that has directed the synthesis of agents such as dofetilide [2]. Likewise, and perhaps not unconnectedly, IKr has been the focus for concern in the field of torsades de pointes risk assessment. However, this has resulted in IKs becoming overlooked as a therapeutic target, and indeed as a target for torsadogenic adverse effects of non-cardiac drugs (so much so that HERG screening is regarded as the sole necessary proarrhythmic drug safety evaluation by many pharmaceutical companies).