[First experience of clinical use of new class III antiarrhythmic agent niferidil in patients with persistent atrial fibrillation and flutter].

The aim of the study was to evaluate the efficacy and safety of administered intravenously niferidil in doses 10, 20 and 30 mkg per kg in patients with persistent atrial fibrillation (AF) and flutter (AFL) for pharmacological cardioversion. The study included 30 patients (22 male) with persistent AF (n = 28) and AFL (n = 2) without structural heart diseases with median arrhythmia duration 6.1 +/- 4.8 months (2 weeks to 24 months). Niferidil was administered as 3 bolus injections (10 mkg per kg each) performed with the interval of 15 minutes. Antiarrhythmic efficacy of niferidil in dose of 10 mkg per kg was 60%, in dose of 20 mkg per kg it was 70%, and in dose of 30 mkg per kg reached 90% prespectively. The part of the patients, in whom QTc prolongation exceeded potentionally dangerous value of 500 mc, was 22.2% (6 of 27). None of the patients developed proarrhythmic side effect as torsade de pointes.

[Experimental and theoretical analysis of the role of cholinergically induced local non-excitability in atrial fibrillation and flutter].

Excitation of vagal nerves results in the emergence of temporarily inexcitable regions in atria. The fact is shown using microelectrode techniques and the mapping of excitation on frog atria isolated together with vago-sympathetic trunks. These regions serve as unidirectional block and functional obstacle provoking reentry-type arrhythmia. The mechanism is defined in terms of a two-dimensional mathematical model which elements were axiomatically set to have the following states: rest, excitation, refractoriness, and vagal inexcitability. With the help of the model we have explained the mechanism of initiation, development and termination of neurogenic tachyarrhythmia. Using micro electrode techniques on an isolated rabbit right atrium we have shown that during intramural nerve excitation as well as in the presence of Ach, there occur inexcitable loci within sinoatrial node (SAN). Probability of development of inexcitability negatively correlates with the velocity of AP upstroke of SAN cells. At maximum upstroke rates higher than 3 V/s, 80 to 90% trials of cholinergic interference resulted in inexcitability. At upstroke rates higher than 12 V/s, inexcitability was not observed. Unlike in amphibians, cholinergically induced inexcitability was not observed in rabbit and canine atria. Cholinergically induced inexcitability in central SAN cells has been simulated with the help of a computer model. The model provides a detailed description of transmembrane current and intracellular ion flows. The computed data are in good agreement with available experimental results.

[Antiarrhythmic Efficacy of a New Class III Antiarrhythmic Drug RG-2.]. / Antiaritmicheskaia aktivnost' preparata III klassa RG-2 na vagotonicheskoi modeli fibrilliatsii predserdii

We studied effects of a new class III antiarrhythmic drug RG-2 in a canine model of vagally-mediated atrial fibrillation (AF). RG-2 was intravenously infused to anesthetized open-chest dogs in progressive doses (5, 10, 20 and 40 mg/kg, n=6) during vagally-induced AF. RG-2 significantly dose-dependently increased atrial effective refractory period (AERP) with and without vagal stimulation, but did not change conduction velocity. Five mg/kg terminated vagally-induced AF in 4 of 6 dogs but did not prevent AF reinduction. However, additional doses of drug 20 and 40 mg/kg successfully terminated AF in 100% as well as prevented AF reinduction in 50% and 72% of cases, respectively. Activation mapping (224 epicardial electrodes) showed that under drug influence there was gradual reduction of wavelet number until termination of the reentrant excitation. AF cycle length increased before AF termination from 91+/-4 to 140+/-8 ms (p<0.01). These changes correlated with drug-induced increasing of AERP. In conclusion, the ability of RG-2 to terminate and prevent reinduction of experimental AF appears to be associated with a significant prolongation of the AERP.

[The role of stretching the sinus node artery in initiation of atrial fibrillation]. / Rol' rastiazheniia arterii sinusovogo uzla v mekhanizme vozniknoveniia fibriliatsii predserdii.

In anaesthetised dogs with open chest (n = 10), against the background of the Gd3+ (a blocking agent of mechano-sensitive ion channels), acetylcholine perfusion induced no significant changes either in probability of atrial fibrillation occurrence or in the paroxysm duration. The Gd3+ did not alter the deceleration of the sinus rhythm either. Therefore the mechanism of spontaneous occurrence of atrial cholinergic fibrillation seems not to be associated with the trigger activity induced by an increased blood pressure in the right atrium.

[The role of atrial pressure in spontaneous initiation of atrial fibrillation in the dog.]. / Vliianie vnutripredserdnogo davleniia na kharakter vozniknoveniia vagotonicheskoi fibrilliatsii predserdii u sobak.

Atrial fibrillation (AF) frequently occurred under conditions associated with atrial dilatation (stretch) or vagal hyperactivity. To study possible role of atrial stretch in spontaneous initiation of vagal AF we compared changes of right atrial pressure (RAP) and activation patterns during AF beginning. In anesthetized open-chest dogs (n=45) AF was induced by stimulation of vagal nerves (VS) (30-60 Hz, 5-10 s train). VS resulted in sinus node arrest (4.7+/-0.7 sec) with subsequent AF initiation in 153 of 229 cases. In 41% of cases of AF initiation the first atrial wave (A(1)) was closely related to ventricular activation (V) with V-A(1) interval of 94+/-5 ms (<> AF). This ventricular excitation induced acute short increase of RAP from 6.6.+/-0.6 to 12.9+/-1.1 mmHg (p<0.00l). Whereas other cases of AF initiation (59%) had no relation to ventricular activation (A(1)-V interval of 1382+/-173 ms) (<> AF). Atrial activation mapping (224 unipolar electrodes) showed that interval A(1)-A(2) of <> AF was significantly shorter than of <>. These data indicate that atrial stretch induced by elevation of RAP may facilitate the induction of AF but do not play a significant role in the mechanism of spontaneous AF initiation in this animal model.

[Electrophysiological experimental study of a novel class III antiarrhythmic drug RG-2]. / Eksperimental'noe élektrofiziologicheskoe issledovanie preparata III klassa RG-2.

The electrophysiologic effects of a new drug, RG-2 were studied on anesthetized open-chest dogs and on rabbit right atrial tissue. RG-2 was manufactured in Chemical-Pharmaceutical Institute in Moscow. Dogs (n=12) were anesthetized with sodium pentobarbital (30 mg/kg, i.v.). An ECG lead II, arterial blood pressure, His bundle electrogram, atrial and ventricular bipolar electrograms were continuously monitored, recorded and then analyzed by a computerized complex for electrophysiological study. Electrophysiological variables, ECG parameters, atrioventricular conduction (His electrogram) and blood pressure were determined after sequential i.v. administration of 1, 5, 10, 20, 40 and 80 ug/kg of RG-2. Interval between injections was 60 min. RG-2 had no significant effect on PQ, QRS, S-A, A-H and H-V intervals, but the drug caused dose-dependent increase of R-R and QT intervals. Moreover, RG-2 dose-dependently increased the atrial and ventricular effective refractory periods (AERP and VERP). Maximal increases of AERP and VERP registered at 5 min after administration of RG-2 (40 microg/kg) were 46+/-2% (p<0.001 vs control) and 23+/-6% (p<0.05 vs control), respectively. In the isolated rabbit right atrial tissue RG-2 (0.01 to 1 microM) had no effects on maximal diastolic potential, action potential amplitude and Vmax, but revealed concentration-dependent increase of action potential duration at 90% repolarization level (APD90%). The maximal effects on APD90% obtained after RG superfusion at 1 microM were 26+/-7% (p<0.001 vs control). We conclude that RG-2 has significant effects of class III antiarrhythmic drugs in vivo and in vitro.

[Effects of verapamil on atrial fibrillation spontaneous initiation in the intact canine heart]. / Vliianie verapamila na spontannoe vozniknovenie fibrilliatsii predserdii u sobak.

L-type Ca(2+) current (I(Ca,L)) has been shown to play a crucial role in initiation of early after depolarization (EAD) in cardiomyocytes. To study the possible role of EAD in spontaneous initiation of atrial fibrillation (AF), we tested the effects of L-type Ca(2+) channel blocker verapamil in canine models of cholinergic-dependent AF. In anesthetized open-chested dogs (n=13) spontaneous AF was induced by two methods: (1) perfusion with acetylcholine (ACh) in normal Tyrode solution at 9 ml/min into the sinus node artery (SNA) and (2) tonic stimulation of the right cervical vagus nerve (5 sec train). In the control, AF was induced in all dogs by perfusion with ACh (2.9+/-0.8 microM, mean+/-SEM) in 96+/-4% of attempts and by vagal stimulation (VS, 59+/-8 Hz) in 74+/-9% of attempts. Verapamil (0.2 mg/kg i.v.) did not alter the AF inducibility both during ACh perfusion and during VS (93+/-4% and 77+/-13%, NS, respectively) in dogs that retained sinus rhythm (n=8). However, verapamil significantly decreased AF inducibility to 50+/-4% and 21+/-13%, respectively, in dogs that passed to AV rhythm (n=5). Verapamil increased duration of both ACh- and vagally-mediated AF from 15+/-2 sec and 15+/-2 sec to 34+/-6 sec and 23+/-4 see (p<0.05 vs. control), respectively. The activation mapping (112 unipolar electrodes) during the initiation of AF did not reveal a difference in epicardial activation patterns before and after verapamil treatment. Inhibiting the I(Ca,L) by verapamil resulted in significant (p<0.05 vs. control) decrease in systolic and diastolic blood pressure, PQ interval prolongation and slowing down of the sinus rate. Verapamil did not affect atrial effective refractory period (AERP) and conduction velocity in the right atria. The reduction of AERP and the deceleration of heart rate by VS (8 Hz) remained unchangeable after verapamil treatment in comparison to control. Thus, the data suggest that the mechanism of spontaneous AF initiation during increased cholinergic activity is not related to EAD in atria.

[Effects of ryanodine receptors block on spontaneous initiation of atrial fibrillation in the intact canine heart]. / Vliianie blokady rianodinovykh retseptorov na spontannoe vozniknovenie fibrilliatsii predserdii u sobak.

To study the possible role of intracellular Ca2+ overload in initiation of cholinergic-dependent atrial fibrillation (AF), we tested the effects of ryanodine in canine models of AF. In anesthetized open-chest dogs (n=10) AF was induced by two methods: (I) perfusion (9 ml/min) with normal Tyrode solution containing acetylcholine (ACh) into the sinus node artery (SNA) and (II) stimulation of the right vagal nerve (VS, 5 sec train). AF was induced in all dogs: by perfusion with ACh (3.7-/+1.5 mcM) into the SNA in 97-/+3% of attempts and by VS in 78-/+6% of attempts. Intravenous infusion of ryanodine (5 mg/kg) did not prevent induction of AF during ACh perfusion (84-/+5%, NS) but completely prevented the induction of AF by VS (4-/+3%, p<0.001). Atrial activation mapping (112 unipolar electrodes) did not show any significant differences between the beginning of ACh-dependent AF in control and after ryanodine treatment. Ryanodine significantly reduced both systolic and diastolic arterial pressures but had no effect on heart rate, atrial effective refractory period (AERP) and conduction velocity for one hour after infusion. Ryanodine, itself, did not exert antivagal activity, so after ryanodine treatment in the presence of VS (8 Hz) the reduction of AERP and the deceleration of heart rate were similar to that in control. These data suggest that ryanodine can suppress the initiation of AF induced by VS but not AF induced by ACh perfusion. We can conclude that the initiation of AF during ACh perfusion unlikely relates to triggering activity induced by intracellular Ca2+ overload. In addition, we suggest that besides ACh some 'unclear' ryanodine sensitive factor(s) contribute to the initiation of AF induced by VS.

Effects of E047/1, a new antiarrhythmic drug, on experimental atrial fibrillation in anesthetized dogs.

Effects of a new antiarrhythmic drug, E047/1, on atrial fibrillation were studied. Atrial conduction velocity and effective refractory period (ERP), electrocardiogram parameters (RR, PR, QRS, QT, and QTc intervals), systolic and diastolic blood pressure, and plasma concentrations of E047/1 were determined during the first 30 min after sequential administration of 1, 3, and 6 mg/kg of E047/1 in polysorbate 60 (Tween 60) to anesthetized, opened-chest dogs with vagally induced atrial fibrillation. Epicardial mapping (using 224 unipolar electrodes) was used to determine atrial fibrillation cycle length and activation sequence before and after drug administration. E0471, 3 mg/kg, prevented atrial fibrillation reinduction, and 6 mg/kg terminated atrial fibrillation. E047/1, 6 mg/kg, increased atrial ERP from 124 +/- 9 to 168 +/- 14 ms (p < 0.05). Conduction velocity decreased from 103 +/- 4 cm/s to 87 +/- 3 cm/s (p < 0.05). Epicardial mapping showed that under drug influence there was gradual reduction of wavelet number until termination of the reentrant excitation. Atrial fibrillation cycle length increased before atrial fibrillation termination from 93 +/- 4 to 137 +/- 12 ms (p < 0.05). The ability of E047/1 to terminate and prevent reinduction of experimental atrial fibrillation appears associated more with a significant prolongation of the atrial ERP than with a slowing of conduction. E047/1 appears to be a promising antifibrillatory agent.

[Trigger activity of ryanodine in mechanism of cholinergic atrial fibrillation in dogs]. / Issledovanie roli triggernoi aktivnosti v mekhanizme vozniknoveniia kholinergicheskoi fibrilliatsii predserdii u sobak s pomoshch'iu rianodina.

Systemic infusion of ryanodine did not prevent induction of atrial fibrillation (AF) during acetylcholine (Ach) perfusion in frogs. The AF, however, appeared later as of the dogs/Ach perfusion start and lasted for a shorter time as compared with the control. The activation mapping of the right atrium showed no significant difference from the control. The findings suggest that the mechanism of AF induction is hardly related to triggering activity, at least in this particular model.

[Isoproterenol potentiates atrial fibrillation induced by acetylcholine]. / Izoproterenol potentsiruet mertsanie predserdii, vyzyvaemoe atsetilkholinom.

A perfusion with normal Tirode solution containing isoproterenol, acetylcholine and their combination into the sinus node artery of the anesthetized open-chest dogs was used to induce atrial fibrillation. The perfusion of isoproterenol, alone, was unable to induce atrial fibrillation, though significantly increased atrial rate. Meanwhile the perfusion of acetylcholine, alone, did induce atrial fibrillation in all animals. The mixed perfusion of isoproterenol and acetylcholine led to decreasing the threshold (minimum) concentration of acetylcholine to induce atrial fibrillation. Herewith, atrial fibrillation appeared at later time from a perfusion start and lasted for more long time. No significant slowing down of sinus rhythm was registered before the initiation of atrial fibrillation. The data suggest that initiation of paroxysmal atrial fibrillation may only be mediated by parasympathetic activity and dependents on a level of adrenergic activity.

Spatial distribution and frequency dependence of arrhythmogenic vagal effects in canine atria.

INTRODUCTION: Prior studies in isolated canine atria demonstrated that acetylcholine-induced reentrant atrial fibrillation (AF) was triggered by multifocal activity in the area of normal impulse origin (sinus node-crista terminalis). The aim of this study was to investigate the activation sequence in AF induced by vagal stimulation (VS) in intact dog hearts. METHODS AND RESULTS: VS (10 to 50 Hz, 1 msec, 15 V, 5-sec trains) induced single or multiple atrial premature depolarizations (APDs), and/or AF in 8 of 10 open chest dogs. Occurrence of APDs and AF increased with increasing VS intensity. Epicardial mapping (254 unipolar electrodes) of both atria showed that APDs as a rule emerged from ectopic sites, often from the right atrial appendage. Activation mapping of the first 10 cycles of AF showed that only a small number (<3 to 4) of unstable reentrant circuits were possible at the same moment. Moreover, most sustained VS-induced AFs were accounted for by a single leading stable reentrant circuit that activated the remainder of the atria. CONCLUSION: (1) Occurrence of vagally induced APDs and AF increases with increasing frequency of VS. (2) VS-induced focal ectopic APDs are widely distributed over the atria. (3) A single APD can be sufficient for initiation of reentrant AF. (4) Despite its high rate of sustained AF, it may be maintained by single stable reentrant circuit. (5) The atrial septum can play an important role in both the initiation and the maintenance of VS-induced AF.

Effects of a new class III antiarrhythmic drug nibentan in a canine model of vagally mediated atrial fibrillation.

Nibentan, a new class III antiarrhythmic drug, is highly effective in patients with atrial flutter and fibrillation. However, its mechanism of action remains unclear. The aim of this study was to investigate the effects of nibentan using a canine model of vagally sustained atrial fibrillation (AF). Nibentan was intravenously infused to anesthetized open-chest dogs during vagally induced AF. Cumulative doses of nibentan (0.063, 0.125, and 0.250 mg/kg) successfully terminated AF in 78, 88, and 100% as well as prevented AF reinduction in 11, 63, and 90% of cases, respectively. All doses of nibentan significantly and rate-independently increased atrial effective refractory period (AERP) with and without vagal stimulation. Activation mapping (224 epicardial electrodes) during AF showed that nibentan reduced the number of simultaneously occurring reentrant wavelets. Herewith the atrial excitation slowed down until conduction failure of reentrant wavelets led to arrhythmia termination. These changes in activation patterns can be accounted for by nibentan-induced increase of AERP (55 +/- 9%, 82 +/- 12%, and 90 +/- 6%; p < 0.01) and wavelength for reentry (47 +/- 7%, 68 +/- 12%, and 72 +/- 4%; p < 0.01) at rapid atrial rates in the presence of vagal stimulation. In conclusion, the high efficacy of nibentan against AF was associated with significant rate-independent increase in AERP and in wavelength, and might be in part explained by block of both delayed rectifier (I(K)) and muscarinic I(K,ACh) currents.

[The role of the interatrial septum in development of supraventricular tachyarrhythmias of vagal origin in dogs]. / Rol' mezhpredserdnoi peregorodki v razvitii supraventriculiarnykh takhiaritmii vagusnoi prirody u sobak.

Patterns of atrial activation of ectopic pulse source during vagal stimulation were studied on atrial epicardial surface and atrial septum in mongrel dogs. Epicardial activation maps were drafted. The findings show that, irrespective of preferred direction of conduction in the atria and septum, the entire atrial myocardium acted as a conducting system. Mapping of the first extrasystolic beats during tachyarrhythmias induced with vagal stimulation, has shown their ectopic origin. The data obtained confirms the suggestion that atrial fibrillation may be due to a single source of arrhythmia in septal area.

[Comparison of atrial premature depolarization topography during vagal stimulation and humoral acetylcholine administration]. / Sravnenie topografii vozniknoveniia predserdnykh ékstravozbuzhdenii pri stimuliatsii vagusa i gumoral'nom vozdeistvii atsetilkholina.

Epicardial atrial mapping in open-chest dogs during different cholinergic influences has shown that, in acetylcholine administration and vagal stimulation, spatial distribution of atrial premature depolarisation (APDs) seems to be similar to prevalence of ectopic sources from both atria and atrial septum. Spatial distribution of the APDs in acetylcholine administration in the sinus node artery was limited to the region of this artery so that the APDs mainly arise from intercaval area of the right atrium and from atrial septum, but never from the left atrium. The latent pacemakers spread over both atria and atrial septum, could participate in initiation of cholinergically-induced APDs and atrial fibrillation. A direct effect of acetylcholine seems to be necessary for development of arrhythmic activity of the latent pacemakers.

[Multielectrode mapping study of proarrhythmic vagal effects in the dog atria]. / Issledovanie metodom mnogokanal'nogo kartirovaniia aritmogennogo deistviia bluzhdaiushchikh nervov v predserdiiakh sobaki.

Epicardial mapping (254 unipolar electrodes) of the dog heart both atria was performed to determine spatial distribution of arrhythmic events. The mapping showed that the first atrial premature depolarisation (APD) emerged from ectopic foci, it showed also specific multifocal patterns suggesting a septal source of tachycardia. The data obtained suggests that vagal stimulation (VS) induces focal ectopic APDs, that APDs and escape beats may be due to the same mechanism of spontaneous depolarization in the absence of a reset from dominant rhythm, that a single VS-induced APD is sufficient for initiation of a reentrant atrial fibrillation.

The electrophysiologic effects of ersentilide on canine hearts.

Ersentilide is a benzamide derivative that has been found effective in several intact animal models of arrhythmia. Cellular studies have indicated it blocks the delayed rectifier, IK, and is a beta 1-adrenoceptor antagonist. We used standard electrophysiologic techniques to study ersentilide's actions on canine Purkinje fiber and atrial and ventricular myocardium. Ersentilide had no effect on maximum diastolic potential, action potential amplitude or Vmax of any of those tissues. Neither did it affect normal Purkinje fiber automaticity. Ersentilide prolonged action potential duration and effective refractory period, and prolonged the duration of Ca(2+)-dependent 'slow response' action potentials. It also suppressed abnormal automaticity in Ba2+ superfused fibers and attenuated isoproterenol-induced automaticity. Although ersentilide increased the magnitude of digitalis-induced delayed afterdepolarizations it neither increased nor suppressed the incidence of digitalis-induced arrhythmias in intact dogs. Because it selectively prolongs action potential duration and refractoriness and induces beta 1-adrenoceptor blockade, ersentilide warrants further consideration as an antiarrhythmic agent.

Combination ethacizin and ethmozin treatment of resistant ventricular ectopy: theoretical, experimental, and clinical study.

Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the "guarded-receptor" model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals < 600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 +/- 13% for 400 and 800 mg/day ethmozin and 18 +/- 12 and 55 +/- 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 +/- 2% in these patients without side effects. In the "nonresistant" but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with "fast-off" and one with "slow-off" kinetics, which may provide a general rationale for choosing drug combinations.

Modulating intraventricular conduction through competition of two class 1 antiarrhythmic agents: experience with ethacizin and lidocaine in canine heart.

The frequency-dependent effects on the intraventricular conduction through the dog heart in situ produced by two class 1 antiarrhythmic drugs, ethacizin and lidocaine, with different kinetic properties were investigated. Conduction delay was measured using stimulation of the His-bundle after pharmacologically induced atrioventricular (AV) block. Electrical events were derived from local epicardial bipolar electrograms at the base of the right ventricle. The stimulation program consisted of several 50-pulse trains with progressively shorter interstimulus intervals (ISI) separated by a l-s pause. Ethacizin (1.5 mg/kg) increased conduction delay by 30% at ISI of 1000 ms, and the effect was enhanced when ISI was shortened to 200 ms; l-s pauses did not significantly increase conduction velocity. Addition of lidocaine (12 mg/kg) strongly potentiated the ethacizin effect at ISI shorter than 300 ms without any noticeable increase in conduction delay at longer intervals. The major result was dramatic acceleration of conduction during the l-s pauses while both drugs were infused. With this combination, conduction delay after pause was shorter than with ethacizin alone, which is consistent with the competition of the drugs for the same binding site inside the sodium channel. Combination of two class 1 compounds in clinical practice may enhance their antiarrhythmic effects without adversely inhibiting normal impulse conduction in the heart. Computer-predicted data were in reasonable agreement with experimental results. The "guarded receptor" model, thus, can provide a simple method for predicting local anesthetic drug interactions in man.