Comparative Effects of Increased Extracellular Potassium and Pacing Frequency on the Class III Activities of Methanesulfonanilide IKr Blockers Dofetilide, d-Sotalol, E-4031, and MK-499

Summary: The methanesulfonanilide-containing Class III agents dofetilide, d-sotalol, E-4031, and MK-499 have been characterized as selective blockers of a rapidly activating component of the cardiac delayed rectifier (IK) K+ current, IKr. In the present studies, the effects of dofetilide (3-30 nM), d-sotalol (10-100 μM), E-4031 (30-300 nM), and MK-499 (30-300 nM) on myocardial effective refractory period (ERP) were assessed in ferret right ventricular papillary muscles in conditions of altered extracellular K+ concentration (K+e normal (4 mM) versus increased (10 mM) concentrations, and of altered pacing frequency (1-3 Hz). With 4 mM K+e, all four agents elicited significant, concentration-dependent ERP increases in the frequency range of 1-3 Hz, and all four agents displayed reverse frequency-dependent activity. Reverse frequency-dependent profiles also were demonstrable in 10 mM K+e at the higher test agent concentrations: dofetilide (10 and 30 nM), d-sotalol (100 μM), E-4031 (100 and 300 nM) and MK-499 (100 and 300 nM). All four agents displayed diminished ERP increases in increased versus normal K+e. Among individual test agents, however, there were differences in magnitudes of diminution of ERP increases observed in increased K+e: The activities of d-sotalol and MK-499 were better maintained in increased K+e than were those of dofetilide and E-4031. As a result of this differential sensitivity increased K+e, significant ERP increases were not demonstrable for dofetilide and E-4031 in simultaneous conditions of increased K+e and rapid pacing, whereas significant activities were maintained with d-sotalol and MK-499 in increased K+e throughout the 1-3-Hz range of pacing frequencies. However, the inherent tendency of myocardial refractoriness to increase in increased K+e, particularly at faster pacing frequencies, played a dominant role in determining the relationship between increased versus normal K+e posttreatment ERP in all Class III treatment groups. This frequency-dependent increment in refractoriness in increased K+e reflected in baseline ERP determined in 10 versus 4 mM K+e, respectively, at frequencies of 1 Hz (163 ± 3 vs. 157 ± 2 ms, p = 0.06), 2 Hz (146 ± 3 vs. 134 ± 2 ms, p < 0.01), and 3 Hz (134 ± 2 vs. 112 ± 2 ms, p < 0.01) tended to offset as well as minimize differences among the IKr blockers in diminution of activity observed in increased K+e. As a consequence, no fundamental differences among the methanesulfonanilide IKr blockers were apparent with regard to the influence of altered pacing frequency and K+e on effects on absolute refractoriness in this experimental preparation.