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Blocking Characteristics of hERG, hNav1.5, and hKvLQT1/hminK after Administration of the Novel Anti‐Arrhythmic Compound AZD7009
Author(s) -
PERSSON FRIDA,
CARLSSON LEIF,
DUKER GÖRAN,
JACOBSON INGEMAR
Publication year - 2005
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1046/j.1540-8167.2005.40427.x
Subject(s) - herg , electrophysiology , medicine , refractory period , long term potentiation , pharmacology , torsades de pointes , voltage clamp , potassium channel , receptor , qt interval
AZD7009 is a novel anti‐arrhythmic compound under development for short‐ and long‐term management of atrial fibrillation and flutter. Electrophysiological studies in animals have shown high anti‐arrhythmic efficacy, predominant action on atrial electrophysiology, and low proarrhythmic activity. The main aim of this study was to characterize the blocking effects of AZD7009 on the human ether‐a‐go‐go‐related gene (hERG), the hNav1.5, and the hKvLQT1/hminK currents. Methods and Results: hERG, hKvLQT1/hminK, and hNav1.5 were expressed in CHO K1 cells. Currents were measured using the whole‐cell configuration of the voltage‐clamp technique. AZD7009 inhibited the hERG current with an IC 50 of 0.6 ± 0.07 μ M (n = 6). AZD7009 1 μ M hyperpolarized the potential for half‐maximal activation from −8.2 ± 0.1 mV to −18.0 ± 0.6 mV (P < 0.001, n = 14) and induced pre‐pulse potentiation at potentials near the activation threshold. The hNav1.5 current was blocked with an IC 50 of 4.3 ± 1.20 μ M at 10 Hz (n = 6) and block developed use‐dependently. Recovery from use‐dependent block was slow, τ= 131 seconds. AZD7009 inhibited the hKvLQT1/hminK current only at high concentrations (IC 50 = 193 ± 20 μ M, n = 6). Conclusion: AZD7009 inhibits both the hERG and the hNav1.5 current, and it is most likely this combined current block that underlies the prolongation of the refractoriness and the low proarrhythmic activity demonstrated in animals in vivo.