BACKGROUND: Dysfunction or pharmacologic inhibition of repolarizing cardiac ionic currents can lead to fatal arrhythmias. The hERG potassium channel underlies the repolarizing current I(Kr), and mutations therein can produce both long and short QT syndromes (LQT2 and SQT1). We previously reported on the diphenylurea compound NS1643, which acts on hERG channels in two distinct ways: by increasing overall conductance and by shifting the inactivation curve in the depolarized direction. OBJECTIVE: The purpose of this study was to determine which of the two components contributes more to the antiarrhythmic effects of NS1643 under normokalemic and hypokalemic conditions. METHODS: The study consisted of mathematical simulation of action potentials in a human ventricular ionic cell model in single cell and string of 100 cells. RESULTS: Regardless of external potassium concentration or diastolic interval used, NS1643 decreases action potential duration and triangulation. For single cells, NS1643 increases the postrepolarization refractory time but shortens the absolute refractory period. In one dimensional simulations, NS1643 increases the vulnerable window for unidirectional block but suppresses the emergence of premature action potentials and unidirectional blocks around APD(90). During normokalemia, shifting the inactivation curve has greater impact than increasing conductance, whereas the opposite occurs during hypokalemia. CONCLUSION: Increased hERG conductance and the depolarizing shift of the inactivation curve both contribute to the antiarrhythmic actions of NS1643, with relative effects dependent on external K(+) concentration.