Effects of EGIS-7229 (S 21407), a novel class III antiarrhythmic drug, on myocardial refractoriness to electrical stimulation in vivo and in vitro

The I-Kr blocker EGIS-7229 (S-21407), displays class Ib and class IV effect s that may alter its pharmacologic profile compared with those of pure I-Kr blockers. Therefore, the concentration- and frequency-dependent effects of EGIS-7229, and of the I-Kr blockers d,l-sotalol and dofetilide, on the eff ective refractory period (ERP) were measured in isolated right ventricular papillary muscle of the rabbit in vitro. The effects of these drugs on righ t ventricular fibrillation threshold (RVFT) at increasing intravenous doses were also determined in anesthetized cats. Dofetilide and d,l-sotalol incr eased ERP in a concentration-dependent manner (dofetilide: 3-100 nM; d,l-so talol: 3-100 muM) with strong reverse frequency dependence at high concentr ations. EGIS-7229 concentration dependently lengthened ERP at 1-30 muM. Its effect on ERP was clearly reverse frequency dependent at 3 muM, but this f eature of the drug diminished at 10 muM and was not apparent at 30 muM The effect of EGIS-7229 (30 muM) on ERP was devoid of reverse frequency depende nce as it was more effective (31%) than dofetilide (16 %) at high-pacing ra te (3 Hz), whereas it was less effective (50%) than dofetilide (70%) at slo w-pacing rate (1 Hz). Reverse frequency-dependent ERP effect of dofetilide (100 nM) was similarly abolished by the addition of lidocaine (30 muM). EGI S-7229 (1-8 mg/kg iv), d,l-sotalol (1-8 mg/kg iv), and dofetilide (10-80 mu g/kg iv) caused a dose-dependent increase in RVFT. The minimum effective do se of d,l-sotalol and EGIS-7229 was 1 and 2 mg/kg, respectively. whereas th at of dofetilide was 10 mug/kg. EGIS-7229 induced a smaller peak effect in RVFT than sotalol or dofetilide. In conclusion, EGIS-7229 markedly increase d refractoriness to electrical stimulation in vitro and in vivo. Compared w ith pure I-Kr blockers, the benefits of EGIS-7229 seem to be a greater leng thening of effective refractory period at rapid stimulation rates, suggesti ng a strong antiarrhythmic action, and a smaller effect at slow stimulation rates, suggesting low potential to induce early afterdepolarizations.