Atrial-selective sodium channel blockers: do they exist?

Abstract

The risk of developing severe ventricular arrhythmias and/or organ toxicity by currently available drugs used to treat atrial fibrillation (AF) has prompted the development of atrial-selective antiarrhythmic agents. Until recently the principal focus has been on development of agents that selectively inhibit the ultra-rapid delayed rectifier outward potassium channels (I Kur), taking advantage of the presence of these channels in atria but not ventricles. Recent experimental studies have demonstrated important atrioventricular differences in biophysical properties of the sodium channel and have identified sodium channel blockers such as ranolazine and chronic amiodarone that appear to take advantage of these electrophysiologic distinctions and act to specifically or predominantly depress sodium channel-mediated parameters in "healthy" canine atria versus ventricles. Atrial-selective/predominant sodium channel blockers such as ranolazine effectively suppress AF in experimental models of AF involving canine isolated right atrial preparations at concentrations that produce little to no effect on ventricular electrophysiologic parameters. These findings point to atrial-selective sodium channel block as a new strategy for the management of AF. The present review examines our current understanding of atrioventricular distinctions between atrial and ventricular sodium channels and our understanding of the basis for atrial selectively of the sodium channel blockers. A major focus will be on the ability of the atrial-selective sodium channel blocking properties of these agents, possibly in conjunction with I Kur and/or I Kr blocking properties, to suppress and prevent the reinduction of AF.

Figure 1

Ranolazine specifically induces prolongation of the effective refractory period (ERP) and development of postrepolarization refractoriness in atria (PRR, the difference between ERP and APD₇₅ in atria and between ERP and APD₉₀ in ventricles; ERP corresponds to APD₇₅ in atria and APD₉₀ in ventricles). CL = 500 ms. C, control. The arrows in panel A illustrate the position on the action potential corresponding to the end of the ERP in atria and ventricles and the effect of ranolazine to shift the end of the ERP in atria but not ventricles. *P < 0.05 versus control. †P < 0.05 versus APD₇₅ values in atria and APD₉₀ in ventricles; (n = 5–18). From Burashnikov et al with permission.

Figure 2

Ranolazine produces a much greater rate-dependent inhibition of the maximal action potential upstroke velocity (V_max) in atria than in ventricles. A, Normalized changes in V_max of atrial and ventricular cardiac preparations paced at a cycle length (CL) of 500 ms. B, Ranolazine prolongs late repolarization in atria but not ventricles, and acceleration of rate leads to elimination of the diastolic interval, resulting in a more positive takeoff potential in atrium and contributing to atrial selectivity of ranolazine. The diastolic interval remains relatively long in ventricles. *P < 0.05 versus control. †P < 0.05 versus respective values of M cell and Purkinje (n = 7–21). From Burashnikov et al with permission.

Figure 3

Frequency-dependent extra block (ie, phasic) and resting (ie, tonic) sodium channel block induced by lidocaine, quinidine, and prajmaline in rabbit superfused atrial and ventricular slice preparations. From Langenfeld et al with permission.

Figure 4

A semiquantitative assessment of atrial selectivity of I_Na blockers based on studies conducted in atrial and ventricular coronary-perfused (Cor-perfused) and superfused (Tissues) preparations, isolated myocytes, and in vivo (see text for details).

Figure 5

Activation and steady-state inactivation in atrial versus ventricular myocytes. A, Current-voltage relation in ventricular and atrial myocytes. Voltage of peak I_Na is more positive and current density is larger in atrial versus ventricular myocytes. B, Summarized steady-state inactivation curves. C, Steady-state inactivation curves before and after addition of 15 μM ranolazine. From Burashnikov et al with permission.

Figure 6

Ranolazine suppresses AF and/or prevents its induction in 2 experimental models involving isolated arterially perfused right atria. A, Ranolazine (10 μM) prevents rapid-pacing induction of AF following pretreatment with acetylcholine (ACh; 0.5 μM). Effective refractory period (ERP) is 140 ms at a cycle length (CL) of 500 ms (left panel). Acceleration of pacing rate from a CL of 500 to 200 ms permits a 1:1 response only during the first 7 beats (right panel). B, Persistent AF induced following pretreatment with ACh (0.5 μM) is suppressed by ranolazine (10 μM). AF is initially converted to flutter (within 17 min) and then to sinus rhythm (17 sec later). C, Rapid-pacing induced nonsustained AF (48-sec duration) induced following ischemia/reperfusion and isoproterenol (ISO, 0.2 μM) (left panel) and the effect of ranolazine to prevent the electrical induction of AF (right panel). In both models, ranolazine causes prominent use-dependent depression of excitability and induction of post-repolarization refractoriness. ECG, pseudoelectrocardiogram; AP, action potential. From Burashnikov et al with permission.