The combined ion channel blocker AZD1305 attenuates late Na current and IKr-induced action potential prolongation and repolarization instability.
OBJECTIVE
To assess the late Na+ current (INalate) blockade by the combined ion channel blocker AZD1305 and its influence on repolarization liability in vitro.


RESULTS
Blockade of INalate and the peak Na+ current (INapeak) by AZD1305 and the effects of E-4031, AZD1305, and lidocaine on repolarization liability following cycle length (CL) changes were examined in dog cardiomyocytes and rabbit-superfused Purkinje fibre (PF) and ventricular muscle (VM) preparations, respectively. In the rabbit preparations, a short-long-short CL sequence was introduced during, and followed by, stimulation at a basic CL of 500 ms in the presence of E-4031, AZD1305, E-4031+AZD1305, or E-4031+lidocaine. The standard deviation of the action potential duration at 90% repolarization (APD90) of the five action potentials following resumption of the basic CL was quantified as APD90 instability. AZD1305 concentration-dependently blocked INalate (IC50=4.3 microM) and INapeak (IC50=66 microM). In PFs, E-4031, but not AZD1305, markedly prolonged APD90 (from 380+/-15 to 597+/-86 ms, P<0.05) after the long CL and augmented APD90 instability (2+/-0.4 to 24+/-6.1 ms, P<0.05), increases significantly attenuated by AZD1305 and lidocaine. In the VM, the APD90 prolongation by E-4031 was quantitatively much smaller, thus augmenting the repolarization heterogeneity between the PF and VM, an increase markedly reduced by AZD1305 and lidocaine.


CONCLUSIONS
By blocking INalate, AZD1305 attenuates excessive APD90 prolongation and repolarization instability following sudden slowing of rhythm implying a low proarrhythmic potential for AZD1305.
Bioscience, AstraZeneca R&D Mölndal, Pepparedsleden 1, S-43183 Mölndal, Sweden.
Birgit
B
Andersson
Najah
N
Abi-Gerges
Leif
L
Carlsson
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D002219:Carbamates / Q000008:administration & dosage*; D002478:Cells, Cultured; D004285:Dogs; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000008:administration & dosage; D016276:Ventricular Function / Q000187:drug effects*
D053961:Azabicyclo Compounds; D002219:Carbamates; D026941:Sodium Channel Blockers; C550721:tert-butyl (2-(7-(2-(4-cyano-2-fluorophenoxy)ethyl)-9-oxa-3,7-diazabicyclo(3.3.1)non3-yl)ethyl)carbamate; D012964:Sodium