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.
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.
Carlsson
Leif
L
AstraZeneca R&D Mölndal Bioscience, S-43183 Mölndal, Sweden. leif.g.carlsson@astrazeneca.com
Andersson
Birgit
B
Linhardt
Gunilla
G
Löfberg
Lena
L
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects*; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D020746:Calcium Channels, L-Type / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D020128:Inhibitory Concentration 50; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008729:Methoxamine / Q000009:adverse effects; D010627:Phenethylamines / Q000009:adverse effects*; D026902:Potassium Channel Blockers / Q000009:adverse effects*; D011817:Rabbits; D013449:Sulfonamides / Q000009:adverse effects*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D008729:Methoxamine; C063533:dofetilide