AZD1305 Exerts Atrial Predominant Electrophysiological Actions and Is Effective in Suppressing Atrial Fibrillation and Preventing Its Reinduction in the Dog

Abstract

Recent development of drugs for the treatment of atrial fibrillation (AF) has focused on atrialselective agents. We examined the atrioventricular differences in sodium channel block of the antiarrhythmic agent AZD1305 in atria and ventricles of anesthetized dogs in vivo, in canine isolated arterially-perfused preparations in vitro and in isolated myocytes using whole-cell patch-clamp techniques. AZD1305 did not change heart rate or blood pressure in vivo but prolonged action potential duration and increased effective refractory period, diastolic threshold of excitation, and conduction time preferentially in atria both in vitro and in vivo. AZD1305 reduced the maximum rate of rise of the action potential (AP) upstroke (V max ) predominantly in atria (-51±10% in atria vs. -31±23% in ventricles; 3 μM; cycle length =500 ms). Fast sodium current (I Na ) was blocked by AZD1305 to a greater degree in atrial vs. ventricular myocytes (particularly tonic inhibition). In coronary-perfused right atria, AZD1305 very effectively prevented induction of persistent acetylcholine-mediated AF and, in a different set of atria, terminated persistent AF (in 5/5 and 7/8 atria, respectively). In conclusion, AZD1305 exerts atrial-predominant sodium channel-blocking effects in vitro and in vivo, and effectively suppresses AF.

Reduced Ventricular Proarrhythmic Potential of the Novel Combined Ion-Channel Blocker AZD1305 Versus Dofetilide in Dogs With Remodeled Hearts

“…Under these conditions, the number of TdP episodes was decreased (2 [1-3] versus 7 [3][4][5][6][7][8][9][10][11]; Pϭ0.05) compared with dofetilide alone.…”

“…7,8 In the normal canine heart, this compound exerts atrial-predominant electrophysiological effects both in vivo and in vitro. 9 In the anesthetized methoxamine-sensitized rabbit model of torsades de pointes ventricular tachyarrhythmia (TdP), intravenous AZD1305 increased the QT interval without inducing ventricular extrasystoles or TdP. 7 Beat-to-beat variability of repolarization duration (BVR of the QT interval) also remained unaltered.…”

“…9,10 It causes an atrial-predominant blockade of I Na (particularly tonic inhibition), which is suggested to translate into high antiarrhythmic efficacy. 9 Previously, the predecessor to AZD1305, AZD7009, was shown to restore sinus rhythm in up to 82% of patients with AF episodes lasting up to 30 days and with minimal proarrhythmic side effects. 29,30 AZD7009 was less …”

Atrial Structure and Function and its Implications for Current and Emerging Treatments for Atrial Fibrillation

“…Studies AZD1305 is able to prolong APD in the atria by prolonging initial depolarisation rate, and the post potential refractory period. 17 AZD 1035 has successfully completed phase I safety trials. Ranolazine is already approved as an anti-anginal agent with demonstrated I Na and I Kr blocking capability in the canine model.…”

QT Response after a Test Dose and during Maintenance Therapy with AZD1305 in Patients with Atrial Fibrillation

“…[4,5] Preclinical evidence suggests that such combined ion channel blockade may provide a favorable balance between antiarrhythmic efficacy and the risk of TdP. [6,7] Moreover, AZD1305 exerts late sodium channel blockade, which is postulated to limit the risk of TdP by reducing transmural dispersion of repolarization. [8,9] The torsadogenic potential of AZD1305 was very low when tested in a rabbit model.…”