Effect of a neuroprotective drug, eliprodil on cardiac repolarisation: importance of the decreased repolarisation reserve in the development of proarrhythmic risk.

1. The aim of this study was to analyse the effects of eliprodil, a noncardiac drug with neuroprotective properties, on the cardiac repolarisation under in vitro circumstances, under normal conditions and after the attenuation of the 'repolarisation reserve' by blocking the inward rectifier potassium current (I(K1)) current with BaCl(2). 2. In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil (1 microm) produced a moderate reverse rate-dependent prolongation of the action potential duration (7.4+/-1.5, 8.9+/-2.1 and 9.9+/-1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=9). 3. This effect was augmented in preparations where I(K1) was previously blocked by BaCl(2) (10 microm). BaCl(2) alone lengthened APD in a reverse frequency-dependent manner (7.0+/-1.3, 14.2+/-1.6 and 28.1+/-2.1% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). When eliprodil (1 microm) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl(2) (12.5+/-1.0, 17.6+/-1.5 and 20.5+/-0.9% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). 4. In the normal Langendorff-perfused rabbit heart, eliprodil (1 microm) produced a significant QT(c) prolongation at 1 Hz stimulation frequency (12.7+/-1.8%, n=9). After the attenuation of the 'repolarisation reserve' by the I(K1) blocker BaCl(2) (10 microm), the eliprodil-evoked QT(c) prolongation was greatly enhanced (28.5+/-7.9%, n=6). In two out of six Langendorff preparations, this QT(c) lengthening degenerated into torsade de pointes ventricular tachycardia. 5. Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (I(Kr)), but slow component (I(Ks)), transient outward current (I(to)) and I(K1) were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole-cell configuration of the patch-clamp technique. 6. The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of I(Kr). However, after the attenuation of the normal 'repolarisation reserve', this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.

Theoretical possibilities for the development of novel antiarrhythmic drugs.

One possible mechanism of action of the available K-channel blocking agents used to treat arrhythmias is to selectively inhibit the HERG plus MIRP channels, which carry the rapid delayed rectifier outward potassium current (I(Kr)). 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 plus minK channel, which carriy the slow delayed rectifier potassium current (I(Ks)), were also considered to treat arrhythmias, including atrial fibrillation (AF). However, I(Ks) 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 (I(to)), 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 I(to), no specific blockers for I(to) are currently available. Similarly, no specific inhibitors for the Kir 2.1, 2.2, 2.3 channels, which carry the inward rectifier potassium current (I(kl)), 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 (I(Kur)). 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 I(Kur)(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 (I(KAch)) in the atria and not in the ventricle during normal vagal tone and after parasympathetic activation. Specific blockers of I(KAch) 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 I(KAch) but none of them proved to be selective. Further research is needed to develop specific K-channel blockers, such as I(Kur)and I(KAch) inhibitors, and to establish their possible therapeutic value.

Multiple cellular electrophysiological effects of azimilide in canine cardiac preparations.

The cellular electrophysiological effect of azimilide (0.1-30 microM) was analyzed in canine ventricular preparations by applying the standard microelectrode and patch-clamp techniques at 37 degrees C. In papillary muscle, the drug prolonged the action potential duration (APD) in a concentration-dependent manner at a cycle length (CL) of 1000 ms. In Purkinje fibers, at the same CL, the concentration-dependent lengthening of the APD was observed in the presence of up to 3 microM azimilide (at 3.0 microM: 24.1+/-4.2%, n=9); at higher drug concentration, no further APD prolongation was observed. Azimilide lengthened APD in a reverse frequency-dependent manner in papillary muscle and Purkinje fibers alike. Azimilide (10 microM) caused a rate-dependent depression in the maximal upstroke velocity of the action potential (V(max)) in papillary muscle. The time and rate constants of the offset and onset kinetics of this V(max) block were 1754+/-267 ms (n=6) and 5.1+/-0.4 beats (n=6), respectively. Azimilide did not prevent the APD shortening effect of 10 microM pinacidil in papillary muscle, suggesting that the drug does not influence the ATP-sensitive K(+) current. Azimilide inhibited the rapid (I(Kr)) and slow component (I(Ks)) of the delayed rectifier K(+) current and the L-type Ca(2+) current (I(Ca)). The estimated EC(50) value of the drug was 0.59 microM for I(Ks), 0.39 microM for I(Kr) and 7.5 microM for I(Ca). The transient outward (I(to)) and the inward rectifier (I(k1)) K(+) currents were not influenced by the drug. It is concluded that the site of action of azimilide is multiple, it inhibits not only K(+) (I(Kr), I(Ks)) currents but, in higher concentrations, it also exerts calcium- and use-dependent sodium channel block.

Comparison of the effect of class IA antiarrhythmic drugs on transmembrane potassium currents in rabbit ventricular myocytes.

BACKGROUND: The blockade of cardiac transmembrane potassium channels, which is commonly seen with various antiarrhythmic drugs, plays an important role in their mechanism of action. We studied and compared the less-explored effects of three Class IA antiarrhythmics on the transient outward current (I(to)) and on the inward rectifier (I(kl)), ATP sensitive (I(KATP)), and delayed rectifier (I(K)) potassium currents in rabbit ventricular myocytes. METHODS AND RESULTS: Transmembrane currents were measured by applying the whole-cell configuration of the patch-clamp technique at 37 degrees C in myocytes enzymatically isolated from rabbit ventricular preparations. Quinidine (10 microM), disopyramide (10 microM), and procainamide (50 microM) were studied at concentrations close to or exceeding the therapeutic plasma level. All studied drugs significantly decreased the amplitude of I(KATP) (activated by 50 microM pinacidil) and I(K) currents. None of them influenced significantly I(kl). The amplitude of I(to) was decreased by quinidine and disopyramide but was not considerably altered by procainamide. The fast inactivation of I(to) was not changed by procainamide and was significantly accelerated by quinidine and disopyramide. CONCLUSION: Although quinidine, disopyramide, and procainamide are all classified as Class IA antiarrhythmics, these drugs had different effects on various potassium currents, which may partially explain their distinct effect on repolarization in various cardiac tissues and on cardiac arrhythmias in clinical settings.

Interaction of different potassium channels in cardiac repolarization in dog ventricular preparations: role of repolarization reserve.

1 The aim of this study was to investigate the possible role of the interaction of different potassium channels in dog ventricular muscle, by applying the conventional microelectrode and whole cell patch-clamp techniques at 37 degrees C. 2 Complete block of I(Kr) by 1 micro M dofetilide lengthened action potential duration (APD) by 45.6+/-3.6% at 0.2 Hz (n=13). Chromanol 293B applied alone at 10 micro M (a concentration which selectively blocks I(Ks)) did not markedly lengthen APD (<7%), but when repolarization had already been prolonged by complete I(Kr) block with 1 micro M dofetilide, inhibition of I(Ks) with 10 micro M chromanol 293B substantially delayed repolarization by 38.5+/-8.2% at 0.2 Hz (n=6). 3 BaCl(2), at a concentration of 10 micro M which blocks I(Kl) without affecting other currents, lengthened APD by 33.0+/-3.1% (n=11), but when I(Kr) was blocked with 1 micro M dofetilide, 10 micro M BaCl(2) produced a more excessive rate dependent lengthening in APD, frequently (in three out of seven preparations) initiating early afterdepolarizations. 4 These findings indicate that if only one type of potassium channels is inhibited in dog ventricular muscle, excessive APD lengthening is not likely to occur. Dog ventricular myocytes seem to repolarize with a strong safety margin ('repolarization reserve'). However, when this normal 'repolarization reserve' is attenuated, otherwise minimal or moderate potassium current inhibition can result in excessive and potentially proarrhythmic prolongation of the ventricular APD. Therefore, application of drugs which are able to block more than one type of potassium channel is probably more hazardous than the use of a specific inhibitor of one given sort of potassium channel, and when simultaneous blockade of several kinds of potassium channel may be presumed, a detailed study is needed to define the determinants of 'repolarization reserve'.