(Circulation. 1995;91:1799-1806.)
© 1995 American Heart Association, Inc.
Articles |
Ibutilide, a Methanesulfonanilide Antiarrhythmic, Is a Potent Blocker of the Rapidly Activating Delayed Rectifier K+ Current (IKr) in AT-1 Cells
Concentration-, Time-, Voltage-, and Use-Dependent Effects
From the Departments of Pharmacology (T.Y., D.J.S., D.M.R.) and Medicine (D.J.S., D.M.R.), Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Dan M. Roden, MD, Division of Clinical Pharmacology, 532 Medical Research Building, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
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 (IKr). However, previous in vitro studies in guinea pig myocytes have indicated that ibutilide does not block IKr 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 IKr 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 IKr blockers, with EC50 values of 20 (n=12) and 12 (n=8) nmol/L, respectively, at +20 mV. The time and voltage dependence of IKr 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 IKr; 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.
Key Words: ibutilide • dofetilide • antiarrhythmic agents • myocytes
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