azd-7009 and Dilatation--Pathologic

To compare the electrophysiological and antiarrhythmic effects of AZD7009, azimilide, and AVE0118 in the acutely dilated rabbit atria in vitro.. 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.. In the dilated rabbit atria, AZD7009, azimilide, and AVE0118 concentration-dependently increased AERP, effectively prevented AF induction, and rapidly restored sinus rhythm.

Topics: Analysis of Variance; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biphenyl Compounds; Dilatation, Pathologic; Heart Atria; Hydantoins; Imidazolidines; In Vitro Techniques; Organic Chemicals; Piperazines; Rabbits