COMPARATIVE EFFECTS OF INCREASED EXTRACELLULAR POTASSIUM AND PACING FREQUENCY ON THE CLASS-III ACTIVITIES OF METHANESULFONANILIDE I-KR BLOCKERS DOFETILIDE, D-SOTALOL, E-4031, AND MK-499

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 (I-K) K+ current, I-Kr. In the present studies, the effects of dofetilide (3-30 nM), D-sotalol(10-100 mu M), 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 Kf concentration ([Ki(+)](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 mu M), 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 I-Kr blockers in diminution of activity observed in increased [K+](e). As a consequence, no fundamental differences among the methanesulfonanilide I-Kr blockers were apparent with regard to the influence of altered pacing frequency and [K+](e) on effects on absolute refractoriness in this experimental preparation. -