Effects of EGIS-7229 (S 21407), a Novel Class III Antiarrhythmic Drug, on Myocardial Refractoriness to Electrical Stimulation In Vivo and In Vitro

The IKr blocker EGIS-7229 (S-21407), displays class Ib and class IV effects that may alter its pharmacologic profile compared with those of pure IKr blockers. Therefore, the concentration- and frequency-dependent effects of EGIS-7229, and of the IKr blockers d,l-sotalol and dofetilide, on the effective refractory period (ERP) were measured in isolated right ventricular papillary muscle of the rabbit in vitro. The effects of these drugs on right ventricular fibrillation threshold (RVFT) at increasing intravenous doses were also determined in anesthetized cats. Dofetilide and d,l-sotalol increased ERP in a concentration-dependent manner (dofetilide3-100 nM; d,l-sotalol3-100 μM) with strong reverse frequency dependence at high concentrations. EGIS-7229 concentration dependently lengthened ERP at 1-30 μM. Its effect on ERP was clearly reverse frequency dependent at 3 μM, but this feature of the drug diminished at 10 μM and was not apparent at 30 μM. The effect of EGIS-7229 (30 μM) on ERP was devoid of reverse frequency dependence as it was more effective (31%) than dofetilide (16%) at high-pacing rate (3 Hz), whereas it was less effective (50%) than dofetilide (70%) at slow-pacing rate (1 Hz). Reverse frequency-dependent ERP effect of dofetilide (100 nM) was similarly abolished by the addition of lidocaine (30 μM). EGIS-7229 (1-8 mg/kg iv), d,l-sotalol (1-8 mg/kg iv), and dofetilide (10-80 μg/kg iv) caused a dose-dependent increase in RVFT. The minimum effective dose of d,l-sotalol and EGIS-7229 was 1 and 2 mg/kg, respectively, whereas that of dofetilide was 10 μg/kg. EGIS-7229 induced a smaller peak effect in RVFT than sotalol or dofetilide. In conclusion, EGIS-7229 markedly increased refractoriness to electrical stimulation in vitro and in vivo. Compared with pure IKr blockers, the benefits of EGIS-7229 seem to be a greater lengthening of effective refractory period at rapid stimulation rates, suggesting a strong antiarrhythmic action, and a smaller effect at slow stimulation rates, suggesting low potential to induce early afterdepolarizations.