Mechanisms of Action of Antiarrhythmic Agent Bertosamil on hKv1.5 Channels and Outward Potassium Current in Human Atrial Myocytes

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Abstract
We analyzed the mechanism of action of the antiarrhythmic agent bertosamil on hKv1.5 channels expressed in Chinese hamster ovary cells (IhKv1.5) and on the outward current (Io) of human atrial myocytes (HAMs) by using the whole cell patch-clamp technique to record current. External application of 10 μM bertosamil inhibitedIhKv1.5, accelerated its time-dependent decay, and slowed its deactivation. When bertosamil was applied at rest or intracellularly (50 μM), it accelerated the rate ofIhKv1.5 inactivation without change of the peak amplitude. At the steady-state effect of intracellular bertosamil, external drug application only inhibitedIhKv1.5. When cesium was the charge carrier, bertosamil inhibited IhKv1.5 but had no effect on its time course. Intracellular tetraethylammonium inhibitedIhKv1.5, suppressed its inactivation, and prevented bertosamil effects. Bertosamil-treatedIhKv1.5 became highly sensitive to the rate of membrane stimulation and to cumulative inactivation phenomenon. In HAMs, bertosamil also increased the rate and extent ofIo inactivation and slowed its recovery from inactivation, whereas after drug applicationIo became highly sensitive to cumulative inactivation phenomenon. In conclusion, bertosamil 1) causes a use-dependent inhibition of the current upon external drug application, and 2) accelerates the rate of current inactivation when applied at rest or intracellularly. These effects result from both an open-channel block and acceleration of the rate of channel inactivation and contribute to the modulation by bertosamil ofIo in HAM.