Electrophysiological and antiarrhythmic effects of the novel antiarrhythmic agent AZD7009: a comparison with azimilide and AVE0118 in the acutely dilated right atrium of the rabbit in vitro.
OBJECTIVE
To compare the electrophysiological and antiarrhythmic effects of AZD7009, azimilide, and AVE0118 in the acutely dilated rabbit atria in vitro.


RESULTS
In the isolated Langendorf-perfused rabbit heart, the atrial effective refractory period (AERP) and the inducibility of atrial fibrillation (AF) were measured at increasing concentrations of AZD7009 (0.1-3 microM), azimilide (0.1-3 microM), and AVE0118 (0.3-10 microM). In separate groups of atria, termination of sustained AF was assessed. In non-dilated atria, the AERP was 82+/-1.3 ms (mean+/-SEM) and AF could not be induced. Dilation significantly reduced the AERP to 49+/-1.0 ms (P<0.001) and 92% of the atria became inducible. Perfusion with AZD7009, azimilide, and AVE0118 concentration-dependently increased the AERP and reduced the AF inducibility. At the highest concentrations of AZD7009, azimilide, and AVE0118, AERP and AF inducibility changed from 50+/-4.5 to 136+/-6.6 ms and 80 to 0% (both P<0.001) from 51+/-3.0 to 105+/-9.9 ms (P<0.001) and 80 to 0% (P<0.01) and from 46+/-2.8 to 85+/-6.0 ms and 90 to 0% (both P<0.001). Restoration of sinus rhythm was seen in 6/6, 5/6, and 5/6 hearts perfused with AZD7009, azimilide, and AVE0118, respectively.


CONCLUSIONS
In the dilated rabbit atria, AZD7009, azimilide, and AVE0118 concentration-dependently increased AERP, effectively prevented AF induction, and rapidly restored sinus rhythm.
Löfberg
Lena
L
AstraZeneca R&D Mölndal, Integrative Pharmacology, Pepparedsleden 1, S-431 83 Mölndal, Sweden.
Jacobson
Ingemar
I
Carlsson
Leif
L
D000704:Analysis of Variance; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D004108:Dilatation, Pathologic; D006325:Heart Atria / Q000187:drug effects*; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D009930:Organic Chemicals / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits
C501729:AVE 0118; C514242:AZD 7009; D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; D006827:Hydantoins; D048289:Imidazolidines; D009930:Organic Chemicals; D010879:Piperazines; C086123:azimilide