Ottó Hála

Role of IKur in Controlling Action Potential Shape and Contractility in the Human Atrium: Influence of Chronic Atrial Fibrillation

Background—The ultrarapid outward current IKur is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of IKur by low concentrations of 4-aminopyridine or the biphenyl derivative AVE 0118 were investigated on right atrial action potentials (APs) in trabeculae from patients in sinus rhythm (SR) or chronic atrial fibrillation (AF). Methods and Results—AP duration at 90% repolarization (APD90) was shorter in AF than in SR (300±16 ms, n=6, versus 414±10 ms, n=15), whereas APD20 was longer (35±9 ms in AF versus 5±2 ms in SR, P<0.05). 4-Aminopyridine (5 &mgr;mol/L) elevated the plateau to more positive potentials from −21±3 to −6±3 mV in SR and 0±3 to +12±3 mV in AF. 4-Aminopyridine reversibly shortened APD90 from 414±10 to 350±10 ms in SR but prolonged APD90 from 300±16 to 320±13 ms in AF. Similar results were obtained with AVE 0118 (6 &mgr;mol/L). Computer simulations of IKur block in human atrial APs predicted secondary increases in ICa,L and in the outward rectifiers IKr and IKs, with smaller changes in AF than SR. The indirect increase in ICa,L was supported by a positive inotropic effect of 4-aminopyridine without direct effects on ICa,L in atrial but not ventricular preparations. In accordance with the model predictions, block of IKr with E-4031 converted APD shortening effects of IKur block in SR into AP prolongation. Conclusions—Whether inhibition of IKur prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.

Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone

The electrophysiological effects of dronedarone, a new nonionidated analogue of amiodarone were studied after chronic and acute administration in dog Purkinje fibres, papillary muscle and isolated ventricular myocytes, and compared with those of amiodarone by applying conventional microelectrode and patch‐clamp techniques. Chronic treatment with dronedarone (2×25 mg−1 kg−1 day p.o. for 4 weeks), unlike chronic administration of amiodarone (50 mg−1 kg−1 day p.o. for 4 weeks), did not lengthen significantly the QTc interval of the electrocardiogram or the action potential duration (APD) in papillary muscle. After chronic oral treatment with dronedarone a small, but significant use‐dependent Vmax block was noticed, while after chronic amiodarone administration a strong use‐dependent Vmax depression was observed. Acute superfusion of dronedarone (10 μM), similar to that of amiodarone (10 μM), moderately lengthened APD in papillary muscle (at 1 Hz from 239.6±5.3 to 248.6±5.3 ms, n=13, P<0.05), but shortened it in Purkinje fibres (at 1 Hz from 309.6±11.8 to 287.1±10.8 ms, n=7, P<0.05). Both dronedarone (10 μM) and amiodarone (10 μM) superfusion reduced the incidence of early and delayed afterdepolarizations evoked by 1 μM dofetilide and 0.2 μM strophantidine in Purkinje fibres. In patch‐clamp experiments 10 μM dronedarone markedly reduced the L‐type calcium current (76.5±0.7 %, n=6, P<0.05) and the rapid component of the delayed rectifier potassium current (97±1.2 %, n=5, P<0.05) in ventricular myocytes. It is concluded that after acute administration dronedarone exhibits effects on cardiac electrical activity similar to those of amiodarone, but it lacks the ‘amiodarone like’ chronic electrophysiological characteristics.

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.

Differential electrophysiologic effects of chronically administered amiodarone on canine Purkinje fibers versus ventricular muscle

Background: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 μM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. Methods and Results: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) (from 227.8 ± 6.3 ms (n = 20) to 262.3 ± 5.2 ms (n = 21; P < .01), but shortened that of Purkinje fibers from 337.6 ± 9.2 (n = 21) to 308.3 ± 7.1 (n = 19; P < .05). Acute superfusion of 5 μM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 ± 13.6 ms to 281.9 ± 11.9 ms (n = 8; P < −05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 μM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 μM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 μM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 μM dofetilide + 20 μM BaCl2 + 2 mM CsCI) in 5 of 6 experiments and caused strong use-dependent Vmax block with relatively fast onset kinetics (nte constant = 1.23 ± 0.13 AP-1, n = 5) and offset (time constant = 364 ± 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 μM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. Conclusions: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

Self-augmentation of the lengthening of repolarization is related to the shape of the cardiac action potential: Implications for reverse rate dependency

Background and purpose:  The aims of the present work were to study the mechanism of the reverse rate dependency of different interventions prolonging cardiac action potential duration (APD).

Frequency-dependent Cardiac Electrophysiologic Effects of Tedisamil: Comparison With Quinidine and Sotalol

Background: Tedisamil is a potent bradycardic/antiischemic drug known to lengthen car diac repolarization by blocking various potassium channels. Recent in vivo experiments revealed that it is an antiarrhythmic agent. It was therefore of interest to compare the cellu lar electrophysiologic effects of tedisamil with those of quinidine and sotalol in isolated car diac preparations. Methods and Results: The conventional microelectrode technique was applied in isolated dog cardiac Purkinje and ventricular muscle fibers and in rabbit left atrial muscle. Tedisamil (1 μM) and sotalol (30 μM) lengthened, while quinidine (10 μM) shortened action potential duration in dog Purkinje fibers. The phase 1 repolarization was delayed by tedisamil and quinidine and not changed by sotalol. In dog ventricular muscle and in rabbit atrial muscle, all three drugs studied lengthened repolarization. In dog Purkinje fiber, tedisamil and sotalol lengthened action potential duration more at slow than at high stimulation frequency (reverse use-dependence). In dog ventricular muscle fibers, the effect of the drugs was not clearly fre quency dependent. In rabbit atrial muscle fibers, the quinidine-evoked repolariration length ening was most pronounced at intermediate cycle lengths (500-1000 ms). Tedisamil and quinidine but not sotalol depressed the maximal rate of depolarization (Vmax), which depended on the stimulation frequency (use-dependence). The nature of the use-dependent Vmax block differed between quinidine and tedisamil. Quinidine decreased Vmax at a relatively wide range of stimulation frequencies while tedisamil decreased Vmax largely at high rate of stimulation. Tedisamil and quinidine prevented or decreased the pinacidil-evoked action potential shortening in dog ventricular muscle, suggesting block of the ATP-dependent potas sium channels (IKATP), while with sotalol such effect was not observed. Conclusions: Although tedisamil, quinidine. and sotalol are known to lengthen the QT inter val, their cellular electrophysiologic effects substantially differ. Tedisamil lengthens repolar ization and prevents pinacidil-evoked action potential duration shortening, suggesting IK(ATP) blockade. Its effect on the Vmax is limited mostly to fast heart rate. These electrophysiologic effects of tedisamil resemble those of chronic amiodarone treatment.

Effect of the Antifibrillatory Compound Tedisamil (KC-8857) on Transmembrane Currents in Mammalian Ventricular Myocytes

The cellular mechanism of action of tedisamil (KC-8857) (TED), a novel antiarrhythmic/antifibrillatory compound, was studied on transmembrane currents in guinea pig, rabbit and dog ventricular myocytes by applying the patch-clamp and the conventional microelectrode technique. In guinea pig myocytes the rapid component of the delayed rectifier potassium current (IKr) was largely diminished by 1 microM TED (from 0.88+/-0.17 to 0.23+/-0.07 pA/pF, n=5, p<0.05), while its slow component (IKs) was reduced only by 5 microM TED (from 8.1+/-0.3 to 4.23+/-0.07 pA/pF, n=5, p<0.05). TED did not significantly change the IKr and IKs kinetics. In rabbit myocytes 1 microM TED decreased the amplitude of the transient outward current (I(to)) from 20.3+/-4.9 to 13.9+/-2.8 pA/pF (n=5, p<0.05), accelerated its fast inactivation time constant from 8.3+/-0.6 to 3.5+/-0.5 ms (n=5, p<0.05) and reduced the ATP-activated potassium current (IKATP) from 38.2+/-11.8 to 18.4+/-4.7 pA/pF (activator: 50 microM cromakalim; n=5, p<0.05). In dog myocytes 2 microM TED blocked the fast sodium current (INa) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (IK1), the inward calcium (ICa) and even the I(to) currents were not affected by TED in concentration as high as 10 microM. The differences in I(to) responsiveness between dog and rabbit are probably due to the different alpha-subunits of I(to) in these species. It is concluded that inhibition of several transmembrane currents, including IKr, IKs, I(to), IKATP and even INa, can contribute to the high antiarrhythmic/antifibrillatory potency of TED, underlying predominant Class III combined with I A/B type antiarrhythmic characteristics.

The cellular electrophysiologic effect of a new amiodarone like antiarrhythmic drug GYKI 16638 in undiseased human ventricular muscle: comparison with sotalol and mexiletine.

The cellular electrophysiologic effect of GYKI 16638, a new antiarrhythmic compound was studied and compared with that of sotalol and mexiletine in undiseased human right ventricular muscle preparation by applying the conventional microelectrode technique. GYKI 16638 (5 microM), at stimulation cycle length of 1000 ms, lengthened action potential duration (APD(90)) from 338.9 +/- 28.6 ms to 385.4 +/- 24 ms (n = 9, p > 0.05). This APD lengthening effect, unlike that of sotalol (30 microM), was rate-independent. GYKI 16638, contrary to sotalol and like mexiletine (10 microM), exerted a use-dependent depression of the maximal rate of depolarization (V(max)) which amounted to 36.4 +/- 11.7% at cycle length of 400 ms (n = 5, p < 0.05) and was characterised with an offset kinetical time constant of 298.6 +/- 70.2 ms. It was concluded that GYKI 16638 in human ventricular muscle shows combined Class IB and Class III antiarrhythmic properties, resembling the electrophysiological manifestation seen after chronic amiodarone treatment.