Micro-electrode arrays in cardiac safety pharmacology: a novel tool to study QT interval prolongation.
Drug-induced QT interval prolongation is now a major concern in safety pharmacology. Regulatory authorities such as the US FDA and the European Medicines Agency require in vitro testing of all drug candidates against the potential risk for QT interval prolongation prior to clinical trials. Common in vitro methods include organ models (Langendorff heart), conventional electrophysiology on cardiac myocytes, and heterologous expression systems of human ether-a-go-go-related gene (hERG) channels. A novel approach is to study electrophysiological properties of cultured cardiac myocytes by micro-electrode arrays (MEA). This technology utilises multi channel recording from an array of embedded substrate-integrated extracellular electrodes using cardiac tissue from the ventricles of embryonic chickens. The detected field potentials allow a partial reconstruction of the shape and time course of the underlying action potential. In particular, the duration of action potentials of ventricular myocytes is closely related to the QT interval on an ECG. This novel technique was used to study reference substances with a reported QT interval prolonging effect. These substances were E4031, amiodarone, quinidine and sotalol. These substances show a significant prolongation of the field potential. However, verapamil, a typical 'false positive' when using the hERG assay does not cause any field potential prolongation using the MEA assay. Whereas the heterologous hERG assay limits cardiac repolarisation to just one channel, the MEA assay reflects the full range of mechanisms involved in cardiac action potential regulation. In summary, screening compounds in cardiac myocytes with the MEA technology against QT interval prolongation can overcome the problem of a single cell assay to potentially report 'false positives'.
Meyer
Thomas
T
Multi Channel Systems MCS GmbH, Reutlingen, Germany. meyer@multichannelsystems.com
Boven
Karl-Heinz
KH
Günther
Elke
E
Fejtl
Michael
M
D000200:Action Potentials; D000818:Animals; D002121:Calcium Channel Blockers / Q000009:adverse effects*; D027682:Cation Transport Proteins / Q000187:drug effects; D002478:Cells, Cultured; D004562:Electrocardiography; D004566:Electrodes; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis; D046228:Microarray Analysis / Q000295:instrumentation*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects; D014700:Verapamil / Q000009:adverse effects*
D002121:Calcium Channel Blockers; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D024642:Potassium Channels, Voltage-Gated; D014700:Verapamil