EFFECTS OF FLECAINIDE, QUINIDINE, AND 4-AMINOPYRIDINE ON TRANSIENT OUTWARD AND ULTRARAPID DELAYED RECTIFIER CURRENTS IN HUMAN ATRIAL MYOCYTES

Antiarrhythmic drugs prevent atrial reentrant arrhythmias by prolongin g atrial action potential duration and refractoriness. The ionic mecha nisms by which antiarrhythmic drugs alter human atrial repolarization are poorly understood. The present study was designed to assess the co ncentration-, voltage-, time- and frequency-dependent effects of the a ntiarrhythmic agents quinidine and flecainide, as well as of the K+ ch annel blocker 4-aminopyridine, on the calcium-independent transient ou tward current (l(to1)) and the ultrarapid delayed rectifier current (l (Kur)) in isolated human atrial myocytes. Quinidine and flecainide blo cked l(to1) at clinically relevant concentrations. Block of (to1) by q uinidine was use and frequency dependent, whereas block by flecainide was frequency independent, and 4-aminopyridine showed use-dependent un blocking. Depolarizing prepulses enhanced flecainide block and reduced 4-aminopyridine block in a fashion suggesting a preferential interact ion with the inactivated state for flecainide and with the resting, cl osed state for 4-aminopyridine. Quinidine block depended on the potent ial of a depolarizing test pulse in a fashion suggesting open channel block. All three drugs accelerated channel inactivation during depolar ization at 1 Hz and failed to block l(to1) during initial current rise , with block appearing with time constants of 6.3 +/- 1.2 msec for fle cainide, 14.5 +/- 4.2 msec for quinidine and 3.0 +/- 0.9 msec for 4-am inopyridine at 16 degrees C, suggesting a role for channel opening in block development. Quinidine blocked l(Kur) clinical concentrations, w hereas flecainide had no effect on l(Kur). Quinidine block of l(Kur) w as voltage dependent, with part of the voltage dependence attributable to open-channel block and the remainder compatible with a blocking si te within the voltage field at a position subject to 23% of the total electrical field. Quinidine's blocking actions on l(Kur) were similar to those previously reported for block of a cardiac K+ channel clone o f the Shaker family (Kv1.5), for which I-Kur is believed to be the equ ivalent native current. These results indicate that flecainide and qui nidine block l(to1), and quinidine blocks l(Kur), in human atrial myoc ytes in a state-dependent fashion. Because drug effects are manifest a t clinically relevant concentrations, and l(to1) and l(Kur) have been shown to be potentially important currents in human atrial repolarizat ion, these findings are relevant to understanding the ionic mechanisms underlying the clinical antiarrhythmic properties of these drugs.