Voltage dependence of cardiac delayed rectifier block by methanesulfonamide class III antiarrhythmic agents.
Voltage-clamp experiments were performed on isolated guinea pig ventricular myocytes to examine the voltage dependence of delayed rectifier block by methanesulfonamide channel blockers. Voltage-dependent channel block, in which block decreases as membrane potential is made more positive, could contribute to the phenomenon of reverse use dependence, in which the magnitude of the drug-induced prolongation in action potential duration (APD) is inversely proportional to stimulation rate. To determine whether such a voltage dependence exists, concentration-response curves were generated for dofetilide, E-4031, sematilide, and D,L-sotalol at test potentials ranging from 0 to 60 mV. All agents blocked current in a manner consistent with selective blockade of the rapidly activating component of delayed rectifier current, IKr. The rank order of potency was E-4031 approximately dofetilide > sematilide > sotalol. Block of tail currents by this class of compounds was more potent after test potentials to +60 mV than after those < or = 0-10 mV. These data are inconsistent with voltage-dependent channel block being a contributing factor to reverse use-dependence and suggest that other mechanisms must be responsible for this phenomenon.
Krafte
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DS
Sterling Winthrop, Inc., Collegeville, PA 19426-0900.
Volberg
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WA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011342:Procainamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology; D013237:Stereoisomerism; D013449:Sulfonamides / Q000494:pharmacology; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D010880:Piperidines; D011725:Pyridines; D013449:Sulfonamides; C062818:sematilide; C063968:E 4031; D013015:Sotalol; D011342:Procainamide; C063533:dofetilide