Assessment of the ion channel-blocking profile of the novel combined ion channel blocker AZD1305 and its proarrhythmic potential versus dofetilide in the methoxamine-sensitized rabbit in vivo.

Abstract

AZD1305 is a novel antiarrhythmic agent under clinical evaluation for management of atrial fibrillation. This study assessed its ion channel-blocking potency by the whole cell patch-clamp technique in vitro and its proarrhythmic liability in anesthetized methoxamine-sensitized rabbits in comparison with dofetilide. AZD1305 predominantly blocked the hERG, the L-type calcium and the hNav1.5 currents in a concentration-dependent manner. In vivo AZD1305 increased the QT interval (from 145 +/- 8 to 196 +/- 18 ms, P < 0.01) without inducing ventricular extrasystoles or torsades de pointes (TdP). In contrast, dofetilide prolonged the QT interval from 161 +/- 3 to 256 +/- 15 ms (P < 0.001) and caused TdP in 12/17 rabbits (P < 0.01 vs. AZD1305). During AZD1305 and dofetilide infusion, the QTend-peak interval maximally increased by 14 +/- 4 and 30 +/- 6 ms (P < 0.05 vs. AZD1305) and the beat-by-beat QT interval variability (quantified as the short-term variability, STV) changed from 2 +/- 0.8 to 2 +/- 0.3 ms (NS) and from 2 +/- 0.2 to 12 +/- 1.1 ms (P < 0.001), respectively. Following dofetilide-induced TdP, 6 rabbits each were injected with saline or AZD1305. In contrast to saline, AZD1305 abbreviated the QT interval (from 275 +/- 25 to 216 +/- 9 ms, P < 0.05), reduced the STV to 1 +/- 0.1 ms (P < 0.001) and suppressed TdP in all 6 rabbits (P < 0.01 vs. saline). In conclusion, AZD1305 can be characterised as a combined ion channel blocker that delays repolarization without increasing beat-by-beat variability of repolarization (BVR) or inducing TdP whereas selective IKr blockade by dofetilide prolongs the QT interval and eventually increases BVR resulting in TdP.

• Authors: Leif Carlsson, Birgit Andersson, Gunilla Linhardt, Lena Löfberg
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 54 Issue 1 Pg. 82-9 (Jul 2009) ISSN: 1533-4023 [Electronic] United States
• PMID: 19528812 (Publication Type: Evaluation Study, Journal Article)

Chemical References

• Anti-Arrhythmia Agents
• Calcium Channel Blockers
• Calcium Channels, L-Type
• Phenethylamines
• Potassium Channel Blockers
• Sulfonamides
• Methoxamine
• dofetilide

Topics

• Action Potentials (drug effects)
• Animals
• Anti-Arrhythmia Agents (adverse effects)
• Arrhythmias, Cardiac (etiology)
• Calcium Channel Blockers (adverse effects)
• Calcium Channels, L-Type (pharmacology)
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Inhibitory Concentration 50
• Long QT Syndrome (chemically induced, physiopathology)
• Male
• Methoxamine (adverse effects)
• Phenethylamines (adverse effects)
• Potassium Channel Blockers (adverse effects)
• Rabbits
• Sulfonamides (adverse effects)
• Time Factors