[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.