Atrial-selective sodium channel block strategy to suppress atrial fibrillation: ranolazine versus propafenone

Ranolazine has been shown to produce atrial-selective depression of sodium channel-dependent parameters and suppress atrial fibrillation (AF) in a variety of experimental models. The present study contrasts the effects of ranolazine and those of a clinically used anti-AF class IC agent, propafenone. Electrophysiological and anti-AF effects of propafenone and ranolazine were compared at clinically relevant concentrations (i.e., 0.3-1.5 and 1-10 μM, respectively) in canine isolated coronary-perfused atrial and ventricular preparations. Transmembrane action potential and pseudo-ECG were recorded. Both ranolazine and propafenone produced atrial-selective prolongation of action potential duration. Propafenone depressed sodium channel-mediated parameters [maximum rate of rise of the action potential upstroke (V(max)), conduction time, and diastolic threshold of excitation] and induced postrepolarization refractoriness to a greater degree than ranolazine, and these effects, unlike those induced by ranolazine, were not or only mildly atrial-selective at normal rates (cycle length 500 ms). At fast pacing rates, however, the effects of propafenone on V(max) and conduction time became atrial-selective, because of the elimination of diastolic interval in atria, but not in ventricles. Propafenone (1.5 μM) and ranolazine (10.0 μM) were effective in preventing the initiation of persistent acetylcholine-mediated AF (6/7 and 9/11 atria, respectively), its termination (8/10 and 8/12 atria, respectively), and subsequent reinduction (8/8 and 7/8 atria, respectively). Thus, propafenone and ranolazine both suppress AF, but ranolazine, unlike propafenone, does it with minimal effects on ventricular myocardium, suggesting a reduced potential for promoting ventricular arrhythmias.     

Novel pharmacological targets for the rhythm control management of atrial fibrillation

Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due to the use of catheter ablation techniques), anti-arrhythmic agents (AADs) remain first line therapy for rhythm control management of AF for most AF patients. When considering efficacy, safety and tolerability, currently available AADs for rhythm control of AF are less than optimal. Ion channel inhibition remains the principal strategy for termination of AF and prevention of its recurrence. Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for rhythm control of AF compared to ion channel-selective blockers. Recent studies suggest that atrial-selective sodium channel block can lead to safe and effective suppression of AF and that concurrent inhibition of potassium ion channels may potentiate this effect. An important limitation of the ion channel block approach for AF treatment is that non-electrical factors (largely structural remodeling) may importantly determine the generation of AF, so that “upstream therapy”, aimed at preventing or reversing structural remodeling, may be required for effective rhythm control management. This review focuses on novel pharmacological targets for the rhythm control management of AF.     

Atrial-selective prolongation of refractory period with AVE0118 is due principally to inhibition of sodium channel activity

The action of AVE0118 to prolong effective refractory period (ERP) in atria but not in ventricles is thought to be due to its inhibition of IKur. However, in nonremodeled atria, AVE0118 prolongs ERP but not action potential duration (APD70-90), which can be explained with the inhibition of sodium but not potassium channel current. ERP, APD, and the maximum rate of increase of the AP upstroke (Vmax) were measured in the canine-isolated coronary-perfused right atrial and in superfused ventricular tissue preparations. Whole-cell patch-clamp techniques were used to measure sodium channel current in HEK293 cells stably expressing SCN5A. AVE0118 (5-10 μM) prolonged ERP (P < 0.001) but not APD70 and decreased Vmax (by 15%, 10 μM, P < 0.05; n = 10 for each). Ventricular ERP, APD90, and Vmax were not changed significantly by 10 μM AVE0118 (all P = ns; n = 7). AVE0118 effectively suppressed acetylcholine-mediated persistent atrial fibrillation. AVE0118 (10 μM) reduced peak current amplitude of SCN5A-WT current by 36.5% ± 6.6% (P < 0.01; n = 7) and shifted half-inactivation voltage (V0.5) of the steady-state inactivation curve from -89.9 ± 0.5 to -96.0 ± 0.9 mV (P < 0.01; n = 7). Our data suggest that AVE0118-induced prolongation of atrial, but not ventricular ERP, is due largely to atrial-selective depression of sodium channel current, which likely contributes to the effectiveness of AVE0118 to suppress atrial fibrillation.     

Comparison of the effects of a transient outward potassium channel activator on currents recorded from atrial and ventricular cardiomyocytes

Effect of NS5806 on Atrial Currents. Introduction: NS5806 activates the transient outward potassium current (I_to) in canine ventricular cells. We compared the effects of NS5806 on canine atrial versus ventricular tissues and myocytes. Methods and Results: NS5806 (10 μM) was evaluated in arterially perfused canine right atrial and right ventricular wedge preparations. In ventricular wedges NS5806 (10 μM) accentuated phase 1 in epicardium (Epi), with little effect in endocardium (Endo), resulting in augmented J‐waves on the ECG. In contrast, application of NS5806 (10 μM) to atrial preparations had no effect on phase 1 repolarization but significantly decreased upstroke velocity (dV/dt) and depressed excitability, consistent with sodium channel block. Current and voltage‐clamp recordings were made in the absence and presence of NS5806 in (10 μM) enzymatically dissociated atrial and ventricular myocytes. In ventricular myocytes, NS5806 increased I_to magnitude by 80% and 16% in Epi and Endo, respectively (at +40 mV). In atrial myocytes, NS5806 increased peak I_to by 25% and had no effect on the sustained current, I_Kur. Under control conditions, I_Na density in atrial myocytes was nearly double that in ventricular myocytes. NS5806 caused a shift in steady‐state mid‐inactivation (V_1/2) from –73.9 ± 0.27 to –77.3 ± 0.21 mV in ventricular and from –82.6 ± 0.12 to –85.1 ± 0.11 mV in atrial cells, resulting in reduction of I_Na in both cell types. Expression of mRNA encoding putative I_Na and I_to channel subunits was evaluated by qPCR. Conclusion: NS5806 produces a prominent augmentation of I_to with little effect on I_Na in the ventricles, but a potent inhibition of I_Na with little augmentation of I_to in atria. (J Cardiovasc Electrophysiol, Vol. 22, pp. 1057‐1066, September 2011)     

Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depressed canine Purkinje fibers. The characteristics of post-repolarization refractoriness

Tissues from diseased hearts are known to exhibit post-repolarization refractoriness and rate-dependent changes of the refractory period that are often inconsistent with changes in action potential duration. To examine the electrophysiological mechanisms responsible for such rate-dependent changes of the refractory period, a narrow inexcitable zone was created by superfusing the central segments of Purkinje fibers with an "ion-free" isotonic sucrose solution. The degree of conduction impairment could be finely regulated by varying the resistance of the extracellular shunt pathway. At intermediate or low levels of block, the refractory period remained unchanged or decreased, respectively, as the rate was increased. At relatively high levels of block, however, we observed marked increases of the refractory period in response to increases in the stimulation rate. The disparity of refractoriness between normally conducting fibers and fibers exhibiting discontinuous conduction characteristics and post-repolarization refractoriness increased dramatically as a function of increasing stimulation rate. With the aid of current clamp techniques, we demonstrate that the differential behavior is due to the interplay between rate-dependent changes in the restitution of excitability at the site beyond the depressed zone secondary to changes in passive and active membrane properties and in the intensity of local circuit current provided to that site by activity generated in the segment proximal to the zone of block. Our data suggest that rate-dependent changes of refractoriness in Purkinje tissue are principally governed by attendant changes in membrane resistance.