Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential.
OBJECTIVE
Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential.


METHODS
Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD(50)) and 90% (APD(90)) of repolarization, STV(APD), triangulation (ratio APD(90)/APD(50)) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz.


RESULTS
LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to I(Kr) blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD.


CONCLUSIONS
LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia.
Abi-Gerges
Najah
N
Safety Pharmacology Department, Safety Assessment UK, AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, Cheshire, UK. najah.abigerges@astrazeneca.com
Valentin
Jean-Pierre
JP
Pollard
Chris E
CE
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011690:Purkinje Fibers / Q000187:drug effects / Q000378:metabolism; D018570:Risk Assessment / Q000379:methods