Theoretical Possibilities for the Development of Novel Antiarrhythmic Drugs

Andras      Varro; Peter      Biliczki; Norbert      Iost; Laszlo      Virag; Otto      Hala; Peter      Kovacs; Peter      Matyus; Julius   Gy.   Papp

Abstract

One possible mechanism of action of the available K-channel blocking agents used to treat arrhythmias is to selectively inhibit the HERG + MIRP channels, which carry the rapid delayed rectifier outward potassium current (IKr). These antiarrhythmics, like sotalol, dofetilide and ibutilide, have been classified as Class III antiarrhythmics. However, in addition to their beneficial effect, they substantially lengthen ventricular repolarization in a reverse-rate dependent manner. This latter effect, in certain situations, can result in life-threatening polymorphic ventricular tachycardia (torsades de pointes). Selective blockers (chromanol 293B, HMR-1556, L-735,821) of the KvLQT1 + minK channel, which carriy the slow delayed rectifier potassium current (IKs), were also considered to treat arrhythmias, including atrial fibrillation (AF). However, IKs activates slowly and at a more positive voltage than the plateau of the action potential, therefore it remains uncertain how inhibition of this current would result in a therapeutically meaningful repolarization lengthening. The transient outward potassium current (Ito), which flows through the Kv 4.3 and Kv 4.2 channels, is relatively large in the atrial cells, which suggests that inhibition of this current may cause substantial prolongation of repolarization predominantly in the atria. Although it was reported that some antiarrhythmic drugs (quinidine, disopyramide, flecainide, propafenone, tedisamil) inhibit Ito, no specific blockers for Ito are currently available. Similarly, no specific inhibitors for the Kir 2.1, 2.2, 2.3 channels, which carry the inward rectifier potassium current (Ik1), have been developed making difficult to judge the possible beneficial effects of such drugs in both ventricular arrhythmias and AF. Recently, a specific potassium channel (Kv 1.5 channel) has been described in human atrium, which carries the ultrarapid, delayed rectifier potassium current (IKur). The presence of this current has not been observed in the ventricular muscle, which raises the possibility that by specific inhibition of this channel, atrial repolarization can be lengthened without similar effect in the ventricle. Therefore, AF could be terminated and torsades de pointes arrhythmia avoided. Several compounds were reported to inhibit IKur (flecainide, tedisamil, perhexiline, quinidine, ambasilide, AVE 0118), but none of them can be considered as specific for Kv 1.5 channels. Similarly to Kv 1.5 channels, acetylcholine activated potassium channels carry repolarizing current (IKAch) in the atria and not in the ventricle during normal vagal tone and after parasympathetic activation. Specific blockers of IKAch can, therefore, also be a possible candidate to treat AF without imposing proarrhythmic risk on the ventricle. At present several compounds (amiodarone, dronedarone, aprindine, pirmenol, SD 3212) were shown to inhibit IKAch, but none of them proved to be selective. Further research is needed to develop specific K-channel blockers, such as IKur and IKAch inhibitors, and to establish their possible therapeutic value.

Keywords: arrhythmia, k-channels, antiarrhythmic drugs