Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes

Abstract

The effects of 17 commonly used antiarrhythmic drugs on the rapidly activating cardiac voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1 and Kv4.2) were studied in the expression system of the Xenopus oocyte. A systematic overview on basic properties was obtained using a simple and restricted experimental protocol (command potentials 10 mV and 50 mV positive to the threshold potential; concentration of 100 micromol/l each). The study revealed that 8 of 17 drugs yielded significant effects (changes >10% of control) on at least one type of potassium channel in the oocyte expression system. These drugs were ajmaline, diltiazem, flecainide, phenytoin, propafenone, propranolol, quinidine and verapamil, whereas the effects of adenosine, amiodarone, bretylium, disopyramide, lidocaine, mexiletine, procainamide, sotalol and tocainide were negligible. The drug effects were characterized by reductions of the potassium currents (except for quinidine and ajmaline). A voltage-dependence of drug effect was found for quinidine, verapamil and diltiazem. The different effect of the drugs was not related to the fast or slow current inactivation of the potassium channels (except for verapamil). Profiles of the individual drug effects at the different potassium channel types were identical for propafenone and flecainide and differed for all other substances. The study demonstrates marked differences in sensitivity to antiarrhythmic drugs within the group of voltage-operated cardiac potassium channel types. Taking the restrictions of the oocyte system into consideration, the findings suggest that several antiarrhythmic drugs exert significant effects at rapidly activating cardiac potassium channels.

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

“…However, Kcna2 overexpression significantly attenuated heart failure–induced abnormal I K in rats, suggesting that upregulation of Kcna2 might be a potential therapeutic strategy for the prevention of ventricular arrhythmias in patients with heart failure. In fact, Kcna2 channels have been identified as a target for antiarrhythmic and bradycardic drugs (class I, III, and IV) in clinical settings 38, 39…”

Effects of diltiazem and propafenone on the inactivation and recovery kinetics of fKv1.4 channel currents expressed in Xenopus oocytes

“…The L-type calcium channel blocker diltiazem and the sodium channel blocker propafenone have been reported to block several cloned potassium channels, including Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, and hERG channel currents [16,[21][22][23][24] . For instance, diltiazem, at concentrations of 0.01 nmol/L to 500 μmol/L, suppressed the hKv1.5 potassium channel expressed in mouse fibroblasts with an estimated IC 50 of 42.3 μmol/L [17] .…”

“…In Xenopus oocytes, diltiazem and propafenone have been reported to reduce fKv1.4 potassium channel currents, and 100 μmol/L diltiazem and 100 μmol/L propafenone were reported to suppress Kv1.4 potassium channel tail currents by 10% and 11%, respectively [16] . Propafenone was shown to be an open channel antagonist of Kv1.4 channel currents [18] , but the mechanism of the drug block was not examined.…”

“…Starting with concentrations of 10 μmol/L, up to 50% of the fKv1.4 channel currents were blocked with 241 μmol/L diltiazem and 103 μmol/L propafenone. Although the concentrations required were higher, in interpreting the results, it has to be further considered that in the oocyte expression system, a fivefold to ten fold higher concentration of antiarrhythmic drugs is needed to obtain an effect comparable to that seen in mammalian cells lines [16] . Thus, it can be assumed that in cardiomyocytes, both diltiazem and propafenone have an even stronger effect on the Kv1.4 channel than that reported in this study in Xenopus oocytes.…”

“…The therapeutic effects are generally believed to be related to the L-type calcium channel (for diltiazem) and the sodium channel (for propafenone). Recent studies demonstrated that diltiazem inhibited the hKv1.5 channel, which conducts ultra rapid delayed rectifier currents (I kur ), and I to , encoded by Kv4.3 by binding to the open and the inactivated states of the channels [15][16][17] . There is evidence that diltiazem decreases Kv1.4 channel currents expressed in the oocytes of Xenopus laevis [16] , and propafenone was shown to be an open channel antagonist of Kv1.4 channel currents [18] , but their detailed characteristics have not been studied.…”