title: Characterization of the in vivo and in vitro electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial and ventricular tissue of the dog.
abstract: This study evaluated the effects of the novel antiarrhythmic agent AZD7009 on atrial and ventricular repolarization and on the Na+-current system, using Vmax as an index. Anesthetized dogs were infused with AZD7009 or azimilide to produce three pseudo steady-state plasma concentrations in vivo. Microelectrode techniques were used to record action potentials and effective refractory period (ERP) in vitro. Whereas AZD7009 concentration-dependently increased atrial ERP (AERP, by 48 +/- 7 milliseconds maximum, P < 0.001 versus vehicle), the increases in ventricular ERP (VERP, 8 +/- 4 milliseconds) and QT interval (2 +/- 5.5 milliseconds) were small and not concentration-dependent. For azimilide, the AERP increase was less, whereas VERP and QT increases were substantially larger than with AZD7009. In vitro, AZD7009 concentration-dependently reduced Vmax and increased action potential duration (APD). ERP was increased through APD lengthening and post-repolarization refractoriness. The suppression of Vmax, but not APD prolongation, showed frequency-dependence. APD and ERP increases were more pronounced in atrial than ventricular tissue: in atria, 2 microM AZD7009 increased APD90 and ERP from 224 +/- 7 to 318 +/- 7 milliseconds and 241 +/- 7 milliseconds to 378 +/- 17 milliseconds; versus 257 +/- 5 to 283 +/- 7 milliseconds and 253 +/- 12 to 300 +/- 11 milliseconds respectively in ventricles. Thus, AZD7009 potently and predominantly increases atrial refractoriness in the dog, with actions mediated by combined effects on repolarization and the Na+-current system.
authors.affiliation: AstraZeneca R&D Mölndal, Integrative Pharmacology, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Carlsson
authors.forename: Denis
authors.initials: D
authors.lastname: Chartier
authors.forename: Stanley
authors.initials: S
authors.lastname: Nattel
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; D015222:Sodium Channels; C086123:azimilide