Ibutilide, a Methanesulfonanilide Antiarrhythmic, Is a Potent Blocker of the Rapidly Activating Delayed Rectifier K + Current (I Kr ) in AT-1 Cells

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Abstract
Background Ibutilide is an action potential–prolonging antiarrhythmic currently in clinical trials. The drug shares structural similarities with E-4031 and dofetilide, specific blockers of the rapidly activating delayed rectifier K + current (I Kr ). However, previous in vitro studies in guinea pig myocytes have indicated that ibutilide does not block I Kr but rather increases a slow inward sodium current. Methods and Results In this study, we compared the effects of ibutilide with those of dofetilide on outward current in mouse atrial tumor myocytes (AT-1 cells), a preparation in which, unlike guinea pig, a typical I Kr is the major delayed rectifier and can be readily recorded in isolation from other currents. In AT-1 cells, ibutilide and dofetilide were both potent I Kr blockers, with EC 50 values of 20 (n=12) and 12 (n=8) nmol/L, respectively, at +20 mV. The time and voltage dependence of I Kr inhibition by the two compounds were virtually identical. The following characteristics were most consistent with open channel block: (1) block increased with depolarizing pulses; (2) block increased with longer pulses; (3) currents deactivated more slowly in the presence of drug, resulting in a “crossover” typical of open channel block; and (4) with repetitive pulsing after drug wash-in, use-dependent block was observed. Conclusions These data suggest that the clinical actions of ibutilide are mediated at least in part by block of I Kr ; an effect on inward currents is not excluded. AT-1 cells are a useful model system for the study of drug block of this important repolarizing current.