T he increased mortality associated with the use of the class Ic agents encainide and flecainide in the Cardiac Arrhythmia Suppression Trial (CAST)' has led to a critical reexamination of the adequacy of existing therapies for the control of cardiac arrhythmias. Although the reasons for the findings in CAST remain unclear, proarrhythmia due to excessive slowing of conduction has been suggested as a possible contributing cause. prolongation at slow heart rates, which might lead to proarrhythmia. This pattern of activity, that is, reduced efficacy at fast heart rates and increased efficacy at slow heart rates, is opposite to that typically observed with class I agents,9 which tend to exhibit greater pharmacological effects (i.e., more conduction slowing) as heart rate is increased. The decline in class III activity at fast heart rates has been attributed to a phenomenon called "reverse" usedependence,8 by which potassium channel block is relieved by depolarization and enhanced by hyperpolarization, the reverse of what occurs with the sodium channel blockers. This particular paradigm for potassium channel block is based on an analysis of the effects of the class Ia agent quinidine on delayed rectifier potassium currents in guinea pig ventricular myocytes.10In the present article, we review briefly the role of myocardial potassium channels as targets for class I and class III antiarrhythmic drug action, and suggest a model for the drug-channel interaction that is most consistent with the information currently available on potassium channel block in several different cardiac preparations. Our investigations indicate that potassium channel block by both class I and class III antiarrhythmic agents is enhanced by depolarization and removed by hyperpolarization, and is therefore identical to the type of use-dependence described previously for drug block of sodium channels. This model is supported by direct measurements of delayed rectifier currents in cat ventricular myocytes that are consistent with drug block and unblock of open channels. Finally, we demonstrate that agents that prolong refractoriness by delaying the recovery of sodium channels carry some intrinsic potential for arrhythmia aggravation because they can introduce nonuniformities in otherwise homogeneous tissue by prolonging the diastolic "window" over which slow conduction and unidirectional block can occur. This effect is greatest for kinetically slow drugs like the class Ic agents.

(Circulation 1990;82:289-293) T he delayed rectifier outward potassium current, IK, is believed to play a major role in repolarizing the cardiac action potential.' Selective block of IK has been shown to underlie the uniform increase in action potential duration (APD) produced by the class III antiarrhythmic agents,2-5 whereas many class I antiarrhythmic agents, such as quinidine and cibenzoline, possess K' channel blocking properties that contribute to their antiarrhythmic drug action as well as to their subclassification as members of class IA.6-8Flecainide is an antiarrhythmic agent with pronounced Na+ channel blocking properties that result in a marked depression of cardiac conduction at therapeutic drug concentrations.910 Ca21 current is also inhibited by flecainide but at somewhat higher concentrations than those noted for Na+ channel block." Although both of these actions would tend to shorten APD, as is typically observed in canine Purkinje fibers12'13 and at high concentrations in ventricular muscle,9 flecainide has been reported to increase ventricular APD in vitro,9'2 and to prolong monophasic ventricular APD in humans. '4 In clinical

The effects of lidocaine on sodium current in cardiac myocytes isolated from cat and guinea pig were investigated using the whole-cell variation of the patch-clamp technique. Lidocaine (43-200 microM) reduced sodium current during repetitive depolarizing pulses in a use-dependent manner. To clarify the nature of the use-dependent block, we characterized the time course of block development using a two-pulse protocol. Two distinct phases of block development were found: a rapid phase (tau = 1-6 msec) having a time course concurrent with the time course of channel activation, and a slower phase (tau = 100-900 msec), which developed after channels inactivated. The amplitude of the block during the rapid phase of development was a steep function of transmembrane voltage over the range of -70 to +20 mV. The voltage-dependence was similar to that for sodium channel activation (sodium conductance) but was too steep to be attributed solely to the passive movement of a singly charged molecule under the influence of the transmembrane voltage gradient. These results suggest that use-dependent block of sodium channels in cardiac tissue may result from an interaction of lidocaine with sodium channels in the activated as well as the inactivated channel states. Possible mechanisms underlying the fast component of block are discussed.

SUMMARY1. Na+ current kinetics were studied in isolated atrial myocytes from the adult cat using the single suction-pipette voltage-clamp technique.2. Current-voltage and conductance-voltage relationships were similar to those described in other cardiac myocyte preparations.3. Analysis of Na+ current decay using single-pulse, double-pulse and tail current measurements were in agreement and demonstrate a second-order process of current decay.4. Voltage dependence of steady-state inactivation curves was not symmetrical, having an inflexion at about -90 mV. These results suggest more than a single inactivation process for Na+ channel in the negative potential region.5. Recovery of Na+ current from inactivation had a sigmoid time course: an initial slow component (delay) followed by a fast and then a second slow component. Increasing the pre-pulse duration slowed the time course of recovery.6. Taken together, the results were consistent with the presence of multiple inactivated states for the atrial myocyte Na+ channel.

The frequency-dependent response of the electrophysiologic effects of amiodarone are similar after 11 days of loading or > or = 1 year of chronic therapy. Amiodarone does not exert frequency-dependent effects on ventricular repolarization; it prolongs refractoriness by both time- and voltage-dependent mechanisms and exerts frequency-dependent effects on ventricular conduction. The absence of amiodarone-induced reverse frequency-dependent effects on repolarization, together with its time-dependent effects on refractoriness may account in part for the high efficacy of the drug and its low propensity to cause torsade de pointes.