title: 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.
abstract: 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 microM), 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 microM), 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.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486.
authors.forename: E P
authors.initials: EP
authors.lastname: Baskin
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D004558:Electric Stimulation; D005289:Ferrets; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers; D011725:Pyridines / Q000494:pharmacology*; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D013015:Sotalol / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D010627:Phenethylamines; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; D013449:Sulfonamides; C063968:E 4031; C087257:L 706000; D013015:Sotalol; C063533:dofetilide; D011188:Potassium