Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential
| Autor: | Najah Abi-Gerges, Jean-Pierre Valentin, Chris E. Pollard |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Pharmacology
Proarrhythmia medicine.medical_specialty Purkinje fibers business.industry Dofetilide medicine.disease Afterdepolarization chemistry.chemical_compound medicine.anatomical_structure chemistry Internal medicine Pharmacodynamics Pinacidil cardiovascular system medicine Cardiology Repolarization Diltiazem business medicine.drug |
| Zdroj: | British Journal of Pharmacology. 159:77-92 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/j.1476-5381.2009.00338.x |
| Popis: | Background and purpose: 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. Experimental approach: Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD50) and 90% (APD90) of repolarization, STV(APD), triangulation (ratio APD90/APD50) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. Key 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 IKr 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 and implications: 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. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text