Lengthening of the effective refractory period (ERP) by EGIS-7229, a class III/Ib/IV drug, and by dofetilide, a selective I-Kr blocker, was compared in normokalemia (NK), hypokalemia (LK), and hyperkalemia (HK) in right ventricular papillary Muscles of rabbits paced at 0.5, 1, and 2 Hz, in vitro, and also during beta-adrenergic activation. In NK, EGIS-7229 (3 and 10 mu M) and dofetilide (30 and 100 nM) similarly lengthened ERP in a steeply reverse frequency-dependent manner. The two compounds produced smaller ER-P prolongations at 0.5 Hz in HK and LK, so rate-dependence of ERP changes decreased. EGIS-7229 lengthened ERP more at 2 Hz than at 0.5 Hz at 10 mu M in LK, that is, the effect of EGIS-7229 turned into positive frequency-dependence from 3 to 10 mu M. Furthermore, EGIS-7229 lengthened ERP at 10 mu M more than dofetilide at 100 nM at 2 Hz Stimulation rate (P < 0.05). Isoproterenol (30 nM) eliminated the effect of dofetilide on ERP, while EGIS-7229 prolonged ERP during beta-adrenergic activation. In conclusion, efficacy of EGIS-7229 was superior to that of dofetilide in LK and during beta-adrenergic Stimulation, suggesting improved antiarrhythmic action for EGIS-7229 under certain conditions in the patient.
