Characterization of the in vivo and in vitro electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial and ventricular tissue of the dog.
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.
Carlsson
Leif
L
AstraZeneca R&D Mölndal, Integrative Pharmacology, Sweden.
Chartier
Denis
D
Nattel
Stanley
S
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
D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D048289:Imidazolidines; D010879:Piperazines; D015222:Sodium Channels; C086123:azimilide