title: Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre.
abstract: AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of AZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. AZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC(50) of 11+/-2 microM. 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 microM E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I(Kr)), and to E-4031 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 lidocaine attenuated the E-4031-induced action potential duration prolongation. In atrial cells, AZD7009, 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 AZD7009 or lidocaine. 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 AZD7009 on action potential duration in atrial tissue suggests that AZD7009, in addition to inhibiting I(Kr), also inhibits other repolarising currents in the atria.
authors.affiliation: AstraZeneca R&D Mölndal, Integrative Pharmacology, S-431 83 Mölndal, Sweden. frida.persson@astrazeneca.com
authors.forename: Frida
authors.initials: F
authors.lastname: Persson
authors.forename: Birgit
authors.initials: B
authors.lastname: Andersson
authors.forename: Göran
authors.initials: G
authors.lastname: Duker
authors.forename: Ingemar
authors.initials: I
authors.lastname: Jacobson
authors.forename: Leif
authors.initials: L
authors.lastname: Carlsson
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000037:antagonists & inhibitors; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009930:Organic Chemicals / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels
chemical_list: C514242:AZD 7009; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009930:Organic Chemicals; D010880:Piperidines; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C063968:E 4031; D008012:Lidocaine