TY - JOUR T1 - Pharmacological Removal of hERG Potassium Channel Inactivation by ICA-105574 JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.059543 SP - mol.109.059543 AU - Aaron C. Gerlach AU - Sally J. Stoehr AU - Neil A. Castle Y1 - 2009/01/01 UR - http://molpharm.aspetjournals.org/content/early/2009/10/05/mol.109.059543.abstract N2 - hERG potassium channel activity helps shape the cardiac action potential and influences its duration. In this study, we report upon the discovery of ICA-105574 (3-nitro-N-(4-phenoxyphenyl) benzamide), a potent and efficacious hERG channel activator with a unique mechanism of action. In whole cell patch-clamp studies of recombinant hERG channels, ICA-105574 steeply potentiated current amplitudes over 10-fold with an EC50 value of 0.5 ± 0.1 μM and a Hill slope of 3.3 ± 0.2. The effect on hERG channels was confirmed as the known hERG channel blockers, E-4031 and BeKm-1, potently blocked the stimulatory effects of ICA-105574. The primary mechanism by which ICA-105574 potentiates hERG channel activity is by removing hERG channel inactivation as ICA-105574 (2 μM) shifts the mid-point of the voltage-dependence of inactivation by >180 mV from -86 mV to +96 mV. In addition to the effects on inactivation, greater concentrations of ICA-105574 (3 μM) produced comparatively small hyperpolarizing shifts (up to 11 mV) in the voltage dependence of channel activation as well as a 2-fold slowing of channel deactivation. In isolated guinea pig ventricular cardiac myocytes, ICA-105574 induced a concentration-dependent shortening of action potential duration (>70%, 3 μM) that could be prevented by pre-incubation with E-4031. In conclusion, we have identified a novel agent that can prevent inactivation of hERG potassium channels. This compound may provide a useful tool to further understand the mechanism by which hERG channels inactivate and affect cardiac function in addition to the role of hERG channels in other cell systems.The American Society for Pharmacology and Experimental Therapeutics ER -