Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.llnon-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refiractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of A-ZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. A-ZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC50 of 11 +/- 2 mu M. The late sodium current in isolated rabbit atrial and ventricular myocytes was also concentration dependently inhibited by AZD7009. Action potentials were recorded during exposure to 5 mu M E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I-Kr), and to E4031 in combination with AZD7009 or lidocaine in rabbit atrial and ventricular tissue and Purkinje fibres. In Purkinje fibres, but not in ventricular tissue, AZD7009 and lidocame attenuated the E-4031-induced action potential duration prolongation. In atrial cells, A-ZD7009, but not lidocaine, further prolonged the E-4031-induced action potential duration. E-4031 induced early afterdepolarisations (EADs) in Purkinje fibres, EADs that were totally suppressed by A-ZD7009 or lidocame. In conclusion, excessive action potential duration prolongation induced by E-4031 was attenuated by AZD7009 and lidocaine in rabbit Purkinje fibre, but not in atrial or ventricular tissue, most likely by inhibiting the late sodium current. Furthermore, the opposite effect by A-ZD7009 on action potential duration in atrial tissue suggests that A-ZD7009, in addition to inhibiting I-Kr, also inhibits other repolarising currents in the atria. Published by Elsevier B.V.