Atypical Antiadrenergic Effect of Refralon as a Mechanism of High Antiarrhythmic Effectiveness.

We studied the effect of Refralon on the electrophysiological properties of the supraventricular myocardium against the background of adrenergic (epinephrine) influence in the zone of the pulmonary veins, the area where 50-90% of atrial arrhythmias is triggered. The experiments were carried out on isolated tissue preparations of Wistar rats. The multichannel microelectrode array technique was used to record action potentials simultaneously in the atrium and in the ostium and distal parts of the pulmonary veins. Epinephrine application (12-50 nM) led to depolarization of the resting potential and the conduction block in the distal part of the pulmonary veins. Refralon (30 µg/kg) restored the resting potential in the distal part of the pulmonary veins. Against the background of epinephrine, Refralon did not significantly change the duration of the action potential at 90% repolarization in comparison with control. At the same time, the comparison drug E-4031 against the background of epinephrine significantly increased the duration of action potential in the atrium and in the ostium of the pulmonary veins, and sotalol increased it only in the ostium. Neither E-4031, nor sotalol restored conduction in their distal part. Refralon has a biphasic effect under conditions of adrenergic stimulation: the fast component is responsible for stabilizing the resting potential in the pulmonary vein and reduces the dispersion of action potential duration in the atrium and pulmonary vein and is also quickly washed away, and the slow component is responsible for the increase of the action potential duration and is slowly washed away.

[Types of Conduction Disturbances in Pulmonary Veins].

Recently, the notion that in 60-80 % of cases the origin of the pulmonary veins (PV) is the place of origin of atrial fibrillation (AF) has become widespread. It has been shown that in this area, under the action of norepinephrine (HA), in the absence of stimulation, an intrinsic rhythm appears. Using two-channel microelectrode leads (from the mouth and distal part of the PV) in rats weighing 350-450 grams, it was found that: 1) in the distal part of PV there are cells with depolarized resting potential (RP) up to -50 mV, which under normal conditions are not excitable; 2) in 17 experiments out of 23, various blocks of excitation conduction along PV were revealed; 3) in 8 experiments out of 23, a reflected excitation wave - echo from PV - was recorded. Myocardium of PV is an extremely heterogeneous medium with a strong variance in the duration of the action potential and variable rate of conduction, which contributes to the occurrence of different types of conduction blocks and causes echoes and other rhythm disturbances.

[The Myocardial Sleeves of the Pulmonary Veins: Potential Implications For Atrial Fibrillation].

Pulmonary veins (PVs) are thought to play an important role in the initiation of atrial fibrillation. However, systematic microelectrode studies from different regions of the left atria and PV myocardium remain limited. METHODS AND RESULTS: A 2-microelectrode technique was used to characterize electrophysiological properties of rat left atrial and PV myocardium, at baseline and during electrical stimulation. PV myocardium was characterized by prolonged action potential duration (APD) (74+/-2 ms in the PV mouth vs. 59+/-3 ms in the left atriul, p<0.01), high degree of APD alternans, and spontaneous depolarizations of resting membrane potential recorded without electrical stimulation. In the distal part of the PV, we found an unexcitable area which was characterized by a depolarized resting potential (50+/-4 mV vs. 82+/-2 mV in the left atrium, p<0.01) and conduction blocks. CONCLUSION: PV myocardium demonstrates a high degree of action potential duration heterogeneity and conduction discontinuities which may form a functional substrate for reentrant arrhythmias and provoke atrial fibrillation.