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.
The effects of altered extracellular K+ concentrations ([K+]o) and pacing cycle lengths (CLs) on the electrophysiological actions of dofetilide (UK-68,798), a potent class III antiarrhythmic agent, were examined in isolated guinea-pig ventricular papillary muscle. At a normal [K+]o (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+]o to 10 mM reduced membrane diastolic potential (MDP), action-potential amplitude (APA), and the maximum rising velocity of the action-potential upstroke (Vmax). 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+]o and at each CL. Even at the short cycle lengths (300 and 500 msec), dofetilide-induced increases in APD90 were not attenuated whether [K+]o 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+]o. Dofetilide may, therefore, be expected to be beneficial in the treatment of cardiac tachyarrhythmias related or unrelated to regional myocardial hyperkalemia during myocardial ischemia.
Yang
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Department of Medical Physiology, University of Tromsø, Norway.
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002462:Cell Membrane / Q000187:drug effects; D004558:Electric Stimulation; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide; D011188:Potassium