Pharmacological activation of rapid delayed rectifier potassium current suppresses bradycardia-induced triggered activity in the isolated guinea pig

Recently, attention has been drawn to compounds that activate the human ether-a-go-go channel potassium channel (hERG), which is responsible for the repolarizing rapid delayed rectifier potassium current (IKr) in the mammalian myocardium. The compound NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N-(3-trifluoromethylphenyl) urea] increases the macroscopic current conducted by the hERG channels by increasing the time constant for channel inactivation, which we have reported earlier. In vitro studies suggest that pharmacological activation is an attractive approach for the treatment of some arrhythmias. We present here data that support that NS3623 affects native IKr and report the effects that activating this potassium current have in the intact guinea pig heart. In Langendorff-perfused hearts, the compound showed a concentration-dependent shortening of action potential duration, which was also de-tected as concentration-dependent shorter QT intervals. There was no sign of action potential triangulation or reverse use dependence. NS3623 decreased QT variability and distinctly decreased the occurrence of extrasystoles in the acutely bra-dypaced hearts. Taken together, the present data strongly sup-port the concept of using hERG activators as a treatment for certain kinds of arrhythmias and suggest further investigation of this new approach. The rapid and slow delayed rectifier potassium currents (IKr and IKs) are required for normal repolarization during the cardiac action potential. The molecular component of IKr current is the voltage-gated potassium channel hERG, prob-ably in association with the -subunit KCNE2 (Sanguinett