Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes.

Abstract

(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

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

“…A major advantage conferred by such a preparation over recordings from native cardiomyocytes is the lack of overlapping and potentially contaminating currents; this facilitates the accurate characterization of drug actions. For example, whilst I K tails from feline myocytes were reported to be sensitive to both E-4031 and FLEC (Follmer & Colatsky, 1990), time-dependent outward current during applied depolarizations was only sensitive to blockade by FLEC in some preparations (Follmer et al, 1992). In subsequent experiments on guinea-pig myocytes (Wang et al, 1996), the presence of overlapping I Ks precluded detailed analysis of the FLEC e ect on I Kr .…”

“…Flecainide is e ective against a variety of supraventricular arrhythmias (Falk & Fogel, 1994) and exhibits a low incidence of QT interval prolongation and torsade de pointes (Lui et al, 1982;Wickers et al, 1988;Sarubbi et al, 1996). Experiments performed on feline ventricular myocytes have shown blockade by¯ecainide of delayed recti®er tail currents consistent with identity as I Kr (Follmer & Colatsky, 1990;Follmer et al, 1992). Limited data from guinea-pig ventricular myocytes also suggest that ecainide can inhibit I Kr (Wang et al, 1996).…”

“…The reason for this discrepancy between the two sets of experiments is not entirely clear. However, although FLECsensitive I K tails were reported to be also sensitive to the I Kr blocker E-4031 (Follmer & Colatsky, 1990;Follmer et al, 1992), the measured activation V 0.5 values (between *+3 and +7 mV) were somewhat more positive than would be expected for pure I Kr , for which V 0.5 usually lies somewhat negative to 0 mV (e.g. Sanguinetti & Jurkiewicz, 1990;.…”

Inhibitory effects of JTV‐519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea‐pig hearts

“…It is wellknown that many antiarrhythmic drugs selectively or nonselectively inhibit I Kr . Flecainide and aprindine were shown to inhibit I Kr (Follmer & Colatsky, 1990;OhmotoSekine et al, 1999) whereas quinidine, cibenzoline and bepridil were reported to block both I Kr and I Ks (Balser et al, 1991;Wang et al, 1996;. In terms of class III antiarrhythmic drugs, sotalol, E-4031 and dofetilide selectively inhibited I Kr (Sanguinetti & Jurkiewicz, 1990;Jurkiewicz & Sanguinetti, 1993).…”

Increase in action potential duration and inhibition of the delayed rectifier outward current IK by berberine in cat ventricular myocytes

“…On repolarization each current trace is followed by a slowly decaying current tail. This current has been identified as the delayed rectifying current (IK) (Follmer & Colatsky, 1990;Furukawa et al, 1992). Berberine decreased the current activated during the depolarizing pulse and the subsequent tail current.…”