Affiliation:
1. 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.
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
163 articles.
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