Micro-electrode arrays in cardiac safety pharmacology -: A novel tool to study QT interval prolongation

被引:92
作者
Meyer, T
Boven, KH
Günther, E
Fejtl, M
机构
[1] Multi Channel Syst MCS GmbH, Reutlingen, Germany
[2] Univ Tubingen, Nat & Med Sci Inst, Reutlingen, Germany
关键词
D O I
10.2165/00002018-200427110-00002
中图分类号
R1 [预防医学、卫生学];
学科分类号
1004 ; 120402 ;
摘要
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, them 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'.
引用
收藏
页码:763 / 772
页数:10
相关论文
共 47 条
[1]   Development of electrical activity in cardiac myocyte aggregates derived from mouse embryonic stem cells [J].
Banach, K ;
Halbach, MD ;
Hu, P ;
Hescheler, J ;
Egert, U .
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2003, 284 (06) :H2114-H2123
[2]   The QT interval [J].
Bednar, MM ;
Harrigan, EP ;
Anziano, RJ ;
Camm, AJ ;
Ruskin, JN .
PROGRESS IN CARDIOVASCULAR DISEASES, 2001, 43 (05) :1-45
[3]  
Bode G, 2002, FUND CLIN PHARMACOL, V16, P105
[4]   ANTIARRHYTHMIC EFFECTS OF POTASSIUM CHANNEL OPENERS IN RHYTHM ABNORMALITIES RELATED TO DELAYED REPOLARIZATION [J].
CARLSSON, L ;
ABRAHAMSSON, C ;
DREWS, L ;
DUKER, G .
CIRCULATION, 1992, 85 (04) :1491-1500
[5]  
Champeroux P, 2000, THERAPIE, V55, P101
[6]   AN EXTRACELLULAR MICROELECTRODE ARRAY FOR MONITORING ELECTROGENIC CELLS IN CULTURE [J].
CONNOLLY, P ;
CLARK, P ;
CURTIS, ASG ;
DOW, JAT ;
WILKINSON, CDW .
BIOSENSORS & BIOELECTRONICS, 1990, 5 (03) :223-234
[7]  
De Ponti F, 2002, DRUG SAFETY, V25, P263
[8]   MEA-Tools: an open source toolbox for the analysis of multi-electrode data with MATLAB [J].
Egert, U ;
Knott, T ;
Schwarz, C ;
Nawrot, M ;
Brandt, A ;
Rotter, S ;
Diesmann, M .
JOURNAL OF NEUROSCIENCE METHODS, 2002, 117 (01) :33-42
[9]  
Elming Hanne, 2002, Card Electrophysiol Rev, V6, P289, DOI 10.1023/A:1016345412555
[10]  
ELSHERIF N, 1991, ARCH MAL COEUR VAISS, V84, P227