Effects of Dofetilide and EGIS-7229, an Antiarrhythmic Agent Possessing Class III, IV, and IB Activities, on Myocardial Refractoriness in Hyperkalemia, Hypokalemia, and During β-Adrenergic Activation in the Rabbit Papillary Muscle In Vitro

Abstract

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 microM) and dofetilide (30 and 100 nM) similarly lengthened ERP in a steeply reverse frequency-dependent manner. The two compounds produced smaller ERP 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 microM in LK, that is, the effect of EGIS-7229 turned into positive frequency-dependence from 3 to 10 microM. Furthermore, EGIS-7229 lengthened ERP at 10 microM 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.