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Z Wang, B Fermini and S Nattel
Department of Medicine, Montreal Heart Institute, Quebec, Canada.
Antiarrhythmic drugs prevent atrial reentrant arrhythmias by prolonging atrial action potential duration and refractoriness. The ionic mechanisms by which antiarrhythmic drugs alter human atrial repolarization are poorly understood. The present study was designed to assess the concentration-, voltage-, time- and frequency-dependent effects of the antiarrhythmic agents quinidine and flecainide, as well as of the K+ channel blocker 4-aminopyridine, on the calcium- independent transient outward current (Ito1) and the ultrarapid delayed rectifier current (IKur) in isolated human atrial myocytes. Quinidine and flecainide blocked Ito1 at clinically relevant concentrations. Block of Ito1 by quinidine was use and frequency dependent, whereas block by flecainide was frequency independent, and 4-aminopyridine showed use-dependent unblocking. Depolarizing prepulses enhanced flecainide block and reduced 4-aminopyridine block in a fashion suggesting a preferential interaction with the inactivated state for flecainide and with the resting, closed state for 4-aminopyridine. Quinidine block depended on the potential of a depolarizing test pulse in a fashion suggesting open channel block. All three drugs accelerated channel inactivation during depolarization at 1 Hz and failed to block Ito1 during initial current rise, with block appearing with time constants of 6.3 +/- 1.2 msec for flecainide, 14.5 +/- 4.2 msec for quinidine and 3.0 +/- 0.9 msec for 4-aminopyridine at 16 degrees C, suggesting a role for channel opening in block development. Quinidine blocked IKur at clinical concentrations, whereas flecainide had no effect on IKur. Quinidine block of IKur was voltage dependent, with part of the voltage dependence attributable to open-channel block and the remainder compatible with a blocking site within the voltage field at a position subject to 23% of the total electrical field. Quinidine's blocking actions on IKur were similar to those previously reported for block of a cardiac K+ channel clone of the Shaker family (Kv1.5), for which IKur is believed to be the equivalent native current. These results indicate that flecainide and quinidine block Ito1, and quinidine blocks IKur, in human atrial myocytes in a state-dependent fashion. Because drug effects are manifest at clinically relevant concentrations, and Ito1 and IKur have been shown to be potentially important currents in human atrial repolarization, these findings are relevant to understanding the ionic mechanisms underlying the clinical antiarrhythmic properties of these drugs.
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