Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias.

Abstract

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.

The calcium-independent transient outward potassium current in isolated ferret right ventricular myocytes. II. Closed state reverse use-dependent block by 4-aminopyridine.

“…Similar results (0.5 or 1 mM 4-AP) were obtained in a total of five myocytes. In none of the myocytes where the effects of 4-AP on tail currents were studied did we ever observe a crossover of the tail currents before and after application of 4-AP (i.e., similar to that observed for open channel block of the delayed rectifier K + current by quinidine: Colatsky et al, 1990;Snyders et al, 1991). The constancy of the (approximate) tail current time constants during the block/unblock cycle suggests that 4-AP does not significantly affect the open-toclosed state transition of deactivating /to channels.…”

“…When the binding of such a rapid flickering blocking compound prevents channel closing or inactivation from developing, the result is a "burst" of longer duration than the normal channel open time. If such a mechanism of block occurs in ferret ventricular/to channels, then it would be expected that the time constants of deactivating tail currents will be prolonged in the presence of 4-AP (e.g., similar to that observed for open channel block of the cardiac delayed rectifier current by quinidine: Colatsky, Follmer, and Starmer, 1990;Snyders, Knoth, Roberds, and Tamkun, 1992).…”

Quinidine‐induced open channel block of K+ current in rat ventricle

“…Nattel, 1991;Rosen et al, 1991). Although its ability to block sodium channels (class I antiarrhythmic actions) has been described in some detail as a use-dependent inhibition (Hille, 1977;Hondeghem & Katzung, 1977;Clarkson & Hondeghem, 1984), the action potential broadening, or class III actions of quinidine are less well understood (Singh & Nadamane, 1985;Hondeghem & Snyders, 1990;Colatsky et al, 1990;Lynch et al, 1992). Part of the reason for this is that in mammalian heart there is a relatively large number of quite diverse potassium (K+) currents (Colatsky et al, 1990;Baumgarten & Fozzard, 1991;Gintant et al, 1991).…”

“…Although its ability to block sodium channels (class I antiarrhythmic actions) has been described in some detail as a use-dependent inhibition (Hille, 1977;Hondeghem & Katzung, 1977;Clarkson & Hondeghem, 1984), the action potential broadening, or class III actions of quinidine are less well understood (Singh & Nadamane, 1985;Hondeghem & Snyders, 1990;Colatsky et al, 1990;Lynch et al, 1992). Part of the reason for this is that in mammalian heart there is a relatively large number of quite diverse potassium (K+) currents (Colatsky et al, 1990;Baumgarten & Fozzard, 1991;Gintant et al, 1991). Inhibitory actions of'quinidine on a number of these K+ currents have been described, including effects on the inward rectifier, IKI, in Purkinje fibre and ventricle (Roden & Hoffman, 1985;Salata & Wasserstrom, 1988;Balser et al, 1991b), the time-and voltage-dependent delayed rectifier potassium currents in guinea-pig ventricle (Hiraoka et al, 1986;Roden et al, 1988;Balser et al, 1991a;Wettwer et al, 1992) and rabbit sinoatrial and atrioventricular nodes (Furukawa et al, 1989), the calciumindependent transient outward K+ current in rabbit atrium (Imaizumi & Giles, 1987), canine cardiac Purkinje cells (Nakayama & Fozzard, 1987) and rat ventricle (Slawsky & Castle, 1994) and the ATP-sensitive K+ current (Undrovinas et al, 1990).…”

Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide.

“…'9 It thus differs from many other class III drugs such as sotalol, dofetilide, and E-4031, which act selectively on the rapid component (IKr). 20 The molecular structures of ambasilide and d-sotalol are shown in Fig 1. The purpose of the present experiments was to evaluate the efficacy of ambasilide in a canine model of AF previously developed in our laboratory '6,21 …”