Mechanisms of destabilization and early termination of spiral wave reentry in the ventricle by a class III antiarrhythmic agent, nifekalant

Abstract

Nifekalant (NF) is a novel class III antiarrhythmic agent that is effective in preventing life-threatening ventricular tachycardia/fibrillation (VT/VF). We investigated mechanisms of destabilization and early termination of spiral-type reentrant VT by NF in a two-dimensional subepicardial myocardial layer of Langendorff-perfused rabbit hearts (n = 21) using a high-resolution optical action potential mapping system. During basic stimulation, NF (0.1 microM) caused uniform prolongation of action potential duration (APD) without affecting conduction velocity and an increase of APD restitution slope. VTs induced by direct current stimulation in the presence of NF were of shorter duration (VTs > 30 s: 2/54 NF vs. 19/93 control). During VTs in control (with visible rotors), the wave front chased its own tail with a certain distance (repolarized zone), and they seldom met each other. The average number of phase singularity (PS) points was 1.31 +/- 0.14 per 665 ms (n = 7). In the presence of NF, the wave front frequently encountered its own tail, causing a transient breakup of the spiral wave or sudden movement of the rotation center (spatial jump of PS). The average number of PS was increased to 1.63 +/- 0.22 per 665 ms (n = 7, P < 0.05) after NF. The mode of spontaneous termination of rotors in control was in most cases (9/10, 90.0%) the result of mutual annihilation of counterrotating wave fronts. With NF, rotors frequently terminated by wave front collision with the atrioventricular groove (12/19, 63.2%) or by trapping the spiral tip in a refractory zone (7/19, 36.8%). Destabilization and early termination of spiral wave reentry induced by NF are the result of a limited proportion of excitable tissue after modulation of repolarization.

Bepridil Facilitates Early Termination of Spiral-Wave Reentry in Two-Dimensional Cardiac Muscle Through an Increase of Intercellular Electrical Coupling

“…The VT was transformed from monomorphic to polymorphic and from sustained to non-sustained. We demonstrated previously that nifekalant, a selective I Kr blocker, caused destabilization and early termination of SW reentry in association with marked prolongation and deformation of FBLs (20). This suggests that the bepridil-induced modification of SW reentry is caused, partly, by the APD prolongation through blockade of I Kr and I Ks .…”

“…In the presence of nifekalant, the wavefront frequently encountered its own tail, causing a transient wave break-up (20). Bepridil, in contrast, destabilized the rotation center of reentry without enhancement of wavefront-tail interactions.…”

Action Potential Characteristics in the Sinus Venosa of Patients With and Without Atrial Flutter

“…The longer MAPD in the SV region cannot be ascribed to higher density of the L-type Ca 2+ inward current (ICa, L) or lower density of the delayed rectifier (IKr or IKs) or inward rectifier (IK1) potassium outward currents, because it has been shown in previous experimental and theoretical studies that an increase in ICa,L or a decrease in IKr, IKs or IK1 is accompanied by an increase in the APD restitution slope. [21][22][23][24][25] The combination of a longer duration and more flattened restitution slope in the MAPs of the SV is a unique property, although the underlying mechanisms are unknown.…”

Opposing Effects of Bepridil on Ventricular Repolarization in Humans Inhomogeneous Prolongation of the Action Potential Duration vs Flattening of Its Restitution Kinetics

“…1,27 Bepridil was shown to prolong the APD in the ventricular muscle of guinea pig dog and rabbit. [28][29][30] The APD prolongation using bepridil in guinea pig, unlike most of other class III drugs, 31,32 was not attenuated remarkably at high stimulation rates, suggesting minimal "reverse use-dependence". 28 Our observation in the human ventricle is concordant with the guinea pig result, because the prolongation of the MAPD90s in the bepridiltreated patients at the shortest and longest CLs tested (330 and 750 ms) was comparable (by 15.0 and 16.8% in the RVOT, and by 8.0 and 10.8% in the RVA compared with the controls).…”