title: Contribution of delayed rectifier and inward rectifier to repolarization of the action potential: pharmacologic separation.
abstract: Outward potassium (K) currents contribute to the repolarization process of cardiac action potentials. There are, however, multiple K currents. Recently, two putatively specific K channel blockers have been developed as potential class III antiarrhythmic agents. E-4031 appears to block specifically a fast component of the delayed rectifier (IK), and RP 58866 is a reported inward rectifier current (IK1) blocker. In the present experiments, we examined the effects of E-4031 and RP 58866 on action potentials recorded from guinea pig papillary muscles to determine whether the properties of IK and IK1 measured in whole-cell experiments would be manifested in distinct effects. Both compounds prolonged the APD50 (action potential duration at 50% repolarization) and APD90 (action potential duration at 90% repolarization). However, RP 58866 did not significantly prolong the action potential at voltages of 0 mV and above, while E-4031 did. The results suggest that preferential IK1 block results in a change in action potential waveform that is distinct from that resulting from block of other outward K currents. This could thus be used as a simple first-pass screening tool in determining a preliminary mechanism of action of class III antiarrhythmics prior to more time-consuming but necessary whole-cell voltage clamp experiments.
authors.affiliation: Searle Research and Development, Skokie, Illinois 60077.
authors.forename: C L
authors.initials: CL
authors.lastname: Martin
authors.forename: K
authors.initials: K
authors.lastname: Chinn
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001578:Benzopyrans; D002839:Chromans; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects; D008839:Microelectrodes; D010210:Papillary Muscles / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D002839:Chromans; D002867:Chromones; D010880:Piperidines; D015221:Potassium Channels; D011725:Pyridines; C063968:E 4031; C063899:terikalant