Effect of Cardioactive Drugs on Action Potential Generation and Propagation in Embryonic Stem Cell-Derived CardiomyocytesReppel M.1,2 · Igelmund P.1 · Egert U.3 · Juchelka F.1 · Hescheler J.1 · Drobinskaya I.1
1Institute for Neurophysiology, University of Cologne2Medical Clinic II, University of Lübeck3Bernstein Center for Computational Neuroscience, Albert-Ludwigs-Universität of Freiburg*The authors contributed equally to the manuscript
Irina Drobinskaya, Jürgen Hescheler
Institute for Neurophysiology, University of Cologne
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Extracellular recordings of spontaneous electrical activity in contracting cardiac clusters differentiated from murine embryonic stem cells enable to study electrophysiological features of this in-vitro cardiac-like tissue as well as effects of pharmacological compounds on its chronotropy and electrical conduction. To test if the microelectrode array (MEA) system could serve as a basis for development of a pharmacological screening tool for cardioactive drugs, we used spontaneously beating outgrowths of three-dimensional ES cell aggregates (“embryoid bodies”, EBs) plated onto substrate-integrated MEAs. The effects of the L-type Ca2+ channel antagonist verapamil and Na+ and K+ channel blockers (tetrodotoxin, 4-aminopyridine, and sparfloxacin) on the deduced interrelated cardiac network function were investigated. Application of 10-6 M verapamil led to arrhythmic spiking with a burst-like pattern; at a higher concentration (10-5 M) the drug caused a sustained negative chronotropy up to complete stop of beating. In the presence of tetrodotoxin a conduction block was observed. Since modulation of K+ channel activity can cause anti- or proarrhythmic effects, the influence of K+ channel blockers, namely 4-aminopyridine and sparfloxacin, was investigated. 4-aminopyridine (2x10-3 M) significantly stabilized beating frequency, while the field potential duration (FPD) was concentration-dependently prolonged up to 2.7-fold. Sparfloxacin (3x10-6 M) stabilized the beating frequency as well. At a higher concentration of sparfloxacin (3x10-5 M), a significant prolongation of the spike duration was registered; application of the drug caused also early afterdepolarizations. The results demonstrate a suitability of the studied in-vitro cardiac cell model for pharmacological drug testing in cardiovascular research.
© 2007 S. Karger AG, Basel
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