Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 19, Issue 5-6, Pages 213-224Publisher
KARGER
DOI: 10.1159/000100628
Keywords
ES cells; EB; MEA; drug testing; arrhythmia
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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 (2x 10(-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. Copyright (c) 2007 S. Karger AG, Basel.
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