Effects of altered extracellular potassium and pacing cycle length on the class III antiarrhythmic actions of dofetilide (UK-68,798) in guinea-pig papillary muscle

Summary

The effects of altered extracellular K⁺ concentrations ([K⁺]₀) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guineapig ventricular papillary muscle. At a normal [K⁺]₀ (4 mM) and at CL between 300 and 5000 msec, dofetilide (10 nM) significantly increased the action-potential duration (APD) and the effective refractory period (ERP), whereas other action-potential parameters were unaffected. Elevation of [K⁺]₀ to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (V_max). These changes were accompanied by a small shortening of APD₉₀, but with an increase in ERP; i.e., the ERP/APD₉₀ ratio was increased. Dofetilide also significantly lengthened APD₉₀ at 10 mM [K⁺]₀ and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD₉₀ were not attenuated whether [K⁺]₀ was at 4 or 10 mM. These results indicate that at various pacing CLs, 10 nM dofetilide increases myocardial APD and ERP to a similar extent without significant reverse use-dependence when the cell membrane is normally polarized or partially depolarized by elevated [K⁺]₀. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.