Effects of Optical Enantiomers CK-4000(S) and CK 4001(R) on Defibrillation and Enhancement of Shock- Induced Extension of Action Potential Duration

Antiarrhythmic Drugs and DFT. Introduction: Class III antiarrhythmics have been reported to lower defibrillation threshold (DFT); however, the mechanism(s) of this effect is unknown. Recent evidence suggests that DFT strength DC shocks may terminate reentrant arrhythmias through prolongation of action potential duration and refractory periods. Since Class III antiarrhythmic drugs prolong repolarization, we examined the hypothesis that these drugs enhance shock-induced action potential duration extension (APDE), which might contribute to lowering of DFT. Methods and Results: In order to investigate the specificity of drug effects on action potential repolarization following a shock, an optical enantiomer with mixed β-blocking and Class III effects (CK-4000) and its enantiomer with “pure” Class III antiarrhythmic effects (CK-4001) were compared against placebo in a canine defibrillation model (n = 8 per group). At the 3 mg/kg dose, the enantiomers nonstereoselectively lowered DFT voltage by 19 ± 15% (CK-4000, P < 0.05 compared to placebo) and 25 ± 12% (CK-4001, P < 0.05 compared to placebo), indicating that Class III antiarrhythmic actions alone were sufficient for this effect. Similarly, CK-4000 and CK-4001 at 3 mg/kg enhanced APDE (P < 0.01 compared to placebo) by 20 ± 11% and 24 ± 17%, respectively. APDF prolongation significantly correlated with reduction in DFT voltage for both CK-4000 (r = -0.55, P < 0.03) and CK4001 (r = -0.63, P < 0.01). At 3 mg/kg, the enantiomers stereoselectively prolonged action potential duration (APD₇₅) by an average of 37 ± 14% (CK-4000, P < 0.001) and 23 ± 14% (CK-4001, P < 0.001), and ventricular effective refractory period (VERP) by 38 ± 15% (CK-4000, P < 0.01) and 27 ± 13% (CK-4001, P < 0.05). Prolongations of APD₇₅ and VERP did not correlate with reductions of DFT in individual dogs. Conclusions: These results show that Class III antiarrhythmics and DFT strength shocks additively delay repolarization, which suggests that drug enhancement of APDE may contribute to their effects on DFT.