M. Németh

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.

Effect of adenosine on sinoatrial and ventricular automaticity of the guinea pig

SummaryIn isolated spontaneously beating right ventricular strips and right atrial preparations of guinea pigs adenosine was found to exert a concentration-dependent suppressing effect on the pacemaker activity. Responsiveness to adenosine was approximately 30-fold higher in ventricular than in atrial preparations. A decrease in the rate of slow diastolic (phase 4) depolarization of Purkinje and sinoatrial nodal fibers proved to be a major determinant of the adenosine-induced alteration in pacemaker activity. It is suggested that adenosine might exert its depressant effect on ventricular automaticity via direct excitation of purine receptors located in the specialized pacemaker fibres of the ventricular tissue.

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

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 (IK1) current with BaCl2. In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil (1 μM) 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). This effect was augmented in preparations where IK1 was previously blocked by BaCl2 (10 μM). BaCl2 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 μM) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl2 (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). In the normal Langendorff‐perfused rabbit heart, eliprodil (1 μM) produced a significant QTc prolongation at 1 Hz stimulation frequency (12.7±1.8%, n=9). After the attenuation of the ‘repolarisation reserve’ by the IK1 blocker BaCl2 (10 μM), the eliprodil‐evoked QTc prolongation was greatly enhanced (28.5±7.9%, n=6). In two out of six Langendorff preparations, this QTc lengthening degenerated into torsade de pointes ventricular tachycardia. Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (IKr), but slow component (IKs), transient outward current (Ito) and IK1 were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole‐cell configuration of the patch‐clamp technique. The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of IKr. However, after the attenuation of the normal ‘repolarisation reserve’, this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.

Neue Entwicklungen der antiarrhythmischen Therapie

Die Autoren sind sich der Schwierigkeit und Komplexitat des im Titel angesprochenen Problems bewust. Ziel der vorliegenden Arbeit ist keineswegs, einen vollstandigen Uberblick uber kunftige Perspektiven der Erforschung neuer antiarrhythmischer Substanzen zu geben, sondern sie ist ein Versuch, die Aufmerksamkeit auf neue Entwicklungen zu lenken, die in Zukunft von Bedeutung sein konnen.

New Trends in Protection from Life-Threatening Arrhythmias

Statistics show that in industrialised countries nearly one-third of the mortality among men under the age of 65 years is due to sudden cardiac death brought about mostly by primary ventricular fibrillation following acute myocardial infarction. These statistics do not include the severe consequences of the seemingly less dangerous supraventricular arrhythmias such as cerebral embolism in patients with atrial fibrillation, exhaustion of the heart due to paroxysmal tachycardia, etc. These facts justify the unceasing efforts to find new ways for the prevention and treatment of cardiac rhythm disturbances. The currently used anti-arrhythmic drugs have very narrow margins of safety, and the cardiologist can hardly evade the problem of treating arrhythmias without undue risk. It is hardly surprising that the search for new effective anti-arrhythmic agents with a broad margin of safety remains one of the most important endeavours in cardiovascular drug research.