Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine

Abstract

Background: The development of selective atrial antiarrhythmic agents is a current strategy for suppression of atrial fibrillation (AF).

Methods and results: Whole-cell patch clamp techniques were used to evaluate inactivation of peak sodium channel current (I(Na)) in myocytes isolated from canine atria and ventricles. The electrophysiological effects of therapeutic concentrations of ranolazine (1 to 10 micromol/L) and lidocaine (2.1 to 21 micromol/L) were evaluated in canine isolated coronary-perfused atrial and ventricular preparations. Half-inactivation voltage of I(Na) was approximately 15 mV more negative in atrial versus ventricular cells under control conditions; this difference increased after exposure to ranolazine. Ranolazine produced a marked use-dependent depression of sodium channel parameters, including the maximum rate of rise of the action potential upstroke, conduction velocity, and diastolic threshold of excitation, and induced postrepolarization refractoriness in atria but not in ventricles. Lidocaine also preferentially suppressed these parameters in atria versus ventricles, but to a much lesser extent than ranolazine. Ranolazine produced a prolongation of action potential duration (APD90) in atria, no effect on APD90 in ventricular myocardium, and an abbreviation of APD90 in Purkinje fibers. Lidocaine abbreviated both atrial and ventricular APD90. Ranolazine was more effective than lidocaine in terminating persistent AF and in preventing the induction of AF.

Conclusions: Our study demonstrates important differences in the inactivation characteristics of atrial versus ventricular sodium channels and a striking atrial selectivity for the action of ranolazine to produce use-dependent block of sodium channels, leading to suppression of AF. Our results point to atrium-selective sodium channel block as a novel strategy for the management of AF.

Figures

Figure 1

Activation and steady-state inactivation in atrial vs ventricular myocytes. A, Current–voltage relation in ventricular and atrial myocytes. Voltage of peak INa is more positive and current density is larger in atrial vs ventricular myocytes. B, Summarized steady-state inactivation curves. The half-inactivation voltage (V0.5) is −88.80±0.19 mV in atrial cells (n=9) and −72.64±0.14 mV in ventricular cells (P<0.001; n=7). Insets show representative atrial and ventricular traces after 1-second conditioning pulses to the indicated potentials. C, Steady-state inactivation curves before and after addition of 15 μmol/L ranolazine. Ranolazine shifts V0.5 from −72.53±0.16 to −74.81 ±0.14 mV (P<0.01) in ventricular myocytes (n=4) and from −86.35±0.19 to −91.38±0.35 mV (P<0.001) in atrial myocytes (n=5).

Figure 2

Effects of ranolazine (A) and lidocaine (B) on transmembrane APs from various atrial and ventricular regions. Shown are representative examples of APs and summary data of the effect of ranolazine and lidocaine on APD90 in atrial and ventricular preparations stimulated at a CL of 500 ms. n=5 to 18. The numbers near the dashed lines depict the differences in APD90/95 induced by ranolazine and lidocaine. CT indicates crista terminalis; PM, pectinate muscle; and Epi, epicardium. *P<0.05 vs respective control.

Figure 3

Ranolazine specifically and lidocaine preferentially induce prolongation of the ERP and development of 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. Ventricular data were obtained from epicardium; atrial data, from pectinate muscle. The arrows in A illustrate the position on the AP corresponding to the end of the ERP in atria and ventricles (ERP is coincident with APD75 in atria and APD90 in ventricles) and the effect of ranolazine to shift the end of the ERP in atria but not ventricles. *P<0.05 vs control; †P<0.05 vs APD75 values in atria and APD90 in ventricles. n=5 to 18.

Figure 4

Ranolazine and lidocaine produce a much greater rate-dependent inhibition of the maximal AP upstroke velocity (Vmax) in atria than in ventricles. A, Normalized changes in Vmax of atrial and ventricular cardiac preparations paced at a CL of 500 ms. “Atria” represent combined pectinate muscle and crista terminalis data. “Ventricles” represent combined epicardial and M-cell data from ventricular wedge. C, Mechanism contributing to rate-dependent atrial selectivity of ranolazine. 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. The diastolic interval remains relatively long in ventricles. *P<0.05 vs control; †P<0.05 vs respective values of M cell and Purkinje. n=7 to 21.

Figure 5

Ranolazine produces a much greater reduction in CV in atria than in ventricles. CV was estimated by measuring conduction time between 2 unipolar electrodes in atria and by the duration of P-wave and QRS complexes of ECG recordings from coronary perfused atrial and ventricular preparations. *P<0.05 vs respective control; †P<0.05 vs respective values at CL of 500 ms. n=6 to 10.

Figure 6

Use-dependent binding/unbinding kinetics of ranolazine and lidocaine to the sodium channel in the ventricle approximated from depression and recovery of the maximum rate of rise of the AP upstroke (Vmax). A, B, Vmax changes after acceleration and deceleration of pacing rate in coronary perfused ventricular wedges. Both development of and recovery of use-dependent block are slower with ranolazine (30 μmol/L) than with lidocaine (21 μmol/L). C, D, Superimposed Vmax deflections obtained during recovery intervals (pacing coupling intervals up to 5000 ms) after the use-dependent Vmax depression at a CL of 300 ms. To be better able to discern measurable changes in Vmax in the ventricles, the concentration of ranolazine was increased to 30 μmol/L for these experiments. Unbinding kinetics of sodium channel blockers are believed to be independent of drug concentration. Under control conditions, there is little to no change in Vmax within the pacing CL range of 300 to 5000 ms.

Figure 7

Ranolazine suppresses AF and/or prevents its induction in 2 experimental models involving isolated arterially perfused right atria. A, Persistent ACh-mediated AF (0.5 μmol/L) is suppressed by ranolazine. AF is initially converted to flutter and then to sinus rhythm. B, Ranolazine prevents rapid-pacing induction of after pretreatment with ACh (0.5 μmol/L). ERP is 140 ms at a CL of 500 ms (left). Acceleration of pacing rate from a CL of 500 to 200 ms permits a 1:1 response only during the first 7 beats (right). C, Rapid-pacing-induced nonsustained AF (48-second duration) induced after ischemia/reperfusion and isoproterenol (ISO, 0.2 μmol/L) (left) and the effect of ranolazine to prevent pacing-induced AF (right). In both models, ranolazine causes prominent use-dependent induction of PRR.