Effects of Electrical Stimulation on hiPSC-CM Responses to Classic Ion Channel Blockers

2020 ◽  
Vol 174 (2) ◽  
pp. 254-265 ◽  
Author(s):  
Feng Wei ◽  
Marc Pourrier ◽  
David G Strauss ◽  
Norman Stockbridge ◽  
Li Pang
Keyword(s):  
Electrical Stimulation ◽  
Ion Channel ◽  
Microelectrode Array ◽  
Field Potential ◽  
Channel Blockers ◽  
Channel Block ◽  
Human Cardiomyocytes ◽  
Ion Channel Blockers ◽  
Rate Dependent ◽  
Pacemaker Channel

Abstract Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold great potential for personalized cardiac safety prediction, particularly for that of drug-induced proarrhythmia. However, hiPSC-CMs fire spontaneously and the variable beat rates of cardiomyocytes can be a confounding factor that interferes with data interpretation. Controlling beat rates with pacing may reduce batch and assay variations, enable evaluation of rate-dependent drug effects, and facilitate the comparison of results obtained from hiPSC-CMs with those from adult human cardiomyocytes. As electrical stimulation (E-pacing) of hiPSC-CMs has not been validated with high-throughput assays, herein, we compared the responses of hiPSC-CMs exposed with classic cardiac ion channel blockers under spontaneous beating and E-pacing conditions utilizing microelectrode array technology. We found that compared with spontaneously beating hiPSC-CMs, E-pacing: (1) reduced overall assay variabilities, (2) showed limited changes of field potential duration to pacemaker channel block, (3) revealed reverse rate dependence of multiple ion channel blockers on field potential duration, and (4) eliminated the effects of sodium channel block on depolarization spike amplitude and spike slope due to a software error in acquiring depolarization spike at cardiac pacing mode. Microelectrode array optogenetic pacing and current clamp recordings at various stimulation frequencies demonstrated rate-dependent block of sodium channels in hiPSC-CMs as reported in adult cardiomyocytes. In conclusion, pacing enabled more accurate rate- and concentration-dependent drug effect evaluations. Analyzing responses of hiPSC-CMs under both spontaneously beating and rate-controlled conditions may help better assess the effects of test compounds on cardiac electrophysiology and evaluate the value of the hiPSC-CM model.

Fluorescence-Based High Throughput Screening Technologies for Natural Chloride Ion Channel Blockers

2018 ◽  
Vol 31 (12) ◽  
pp. 1332-1338 ◽  
Author(s):  
Rong Xu ◽  
Yuan Xiao ◽  
Yan Liu ◽  
Bo Wang ◽  
Xing Li ◽  
...  
Keyword(s):  
Ion Channel ◽  
High Throughput ◽  
High Throughput Screening ◽  
Chloride Ion ◽  
Channel Blockers ◽  
Ion Channel Blockers

scholarly journals Is Lipid Bilayer Binding a Common Property of Inhibitor Cysteine Knot Ion-Channel Blockers?

2007 ◽  
Vol 93 (4) ◽  
pp. L20-L22 ◽  
Author(s):  
Yevgen O. Posokhov ◽  
Philip A. Gottlieb ◽  
Michael J. Morales ◽  
Frederick Sachs ◽  
Alexey S. Ladokhin
Keyword(s):  
Ion Channel ◽  
Lipid Bilayer ◽  
Common Property ◽  
Channel Blockers ◽  
Ion Channel Blockers

Compartmental Model of Vertebrate Motoneurons for Ca2+-Dependent Spiking and Plateau Potentials Under Pharmacological Treatment

1997 ◽  
Vol 78 (6) ◽  
pp. 3371-3385 ◽  
Author(s):  
Victoria Booth ◽  
John Rinzel ◽  
Ole Kiehn
Keyword(s):  
Ion Channel ◽  
Compartmental Model ◽  
Ionic Currents ◽  
Channel Blockers ◽  
Spinal Motoneurons ◽  
Plateau Potentials ◽  
Firing Patterns ◽  
Calcium Dependent ◽  
Ion Channel Blockers ◽  
Experimental Effect

Booth, Victoria, John Rinzel, and Ole Kiehn. Compartmental model of vertebrate motoneurons for Ca2+-dependent spiking and plateau potentials under pharmacological treatment. J. Neurophysiol. 78: 3371–3385, 1997. In contrast to the limited response properties observed under normal experimental conditions, spinal motoneurons generate complex firing patterns, such as Ca2+-dependent regenerative spiking and plateaus, in the presence of certain neurotransmitters and ion-channel blockers. We have developed a quantitative motoneuron model, based on turtle motoneuron data, toinvestigate the roles of specific ionic currents and the effects of their soma and dendritic distribution in generating these complex firing patterns. In addition, the model is used to explore the effects of multiple ion channel blockers and neurotransmitters that are known to modulate motoneuron firing patterns. To represent the distribution of ionic currents across the soma and dendrites, the model contains two compartments. The soma compartment, representing the soma and proximal dendrites, contains Hodgkin-Huxley-like sodium ( I Na) and delayed rectifier K+ ( I K−dr) currents, an N-like Ca2+ current ( I Ca−N), and a calcium-dependent K+ current [ I K(Ca)]. The dendritic compartment, representing the lumped distal dendrites, contains, in addition to I Ca−N and I K(Ca) as in the soma, a persistent L-like calcium current ( I Ca−L). We determined kinetic parameters for I Na, I K−dr, I Ca−N, and I K(Ca) in order to reproduce normal action-potential firing observed in turtle spinal motoneurons, including fast and slow afterhyperpolarizations (AHPs) and a linear steady-state frequency-current relation. With this parameter set as default, a sequence of pharmacological manipulations were systematically simulated. A small reduction of I K−dr [mimicking the experimental effect of tetraethylammonium (TEA) in low concentration] enhanced the slow AHP and caused calcium spiking (mediated by I Ca−N) when I Na was blocked. Firing patterns observed experimentally in high TEA [and tetrodotoxin (TTX)], namely calcium spikes riding on a calcium plateau, were reproduced only when both I K−dr and I K(Ca) were reduced. Dendritic plateau potentials, mediated by I Ca−L, were reliably unmasked when I K(Ca) was reduced, mimicking the experimental effect of the bee venom apamin. The effect of 5-HT, which experimentally induces the ability to generate calcium-dependent plateau potentials but not calcium spiking, was reproduced in the model by reducing I K(Ca) alone. The plateau threshold current level, however, was reduced substantially if a simultaneous increase in I Ca−L was simulated, suggesting that serotonin (5-HT) induces plateau potentials by regulating more than one conductance. The onset of the plateau potential showed significant delays in response to near-threshold, depolarizing current steps. In addition, the delay times were sensitive to the current step amplitude. The delay and its sensitivity were explained by examining the model's behavior near the threshold for plateau onset. This modeling study thus accurately accounts for the basic firing behavior of vertebrate motoneurons as well as a range of complex firing patterns invoked by ion-channel blockers and 5-HT. In addition, our computational results support the hypothesis that the electroresponsiveness of motoneurons depends on a nonuniform distribution of ionic conductances, and they predict modulatory effects of 5-HT and properties of plateau activation that have yet to be tested experimentally.

Discrimination of the effects of three cardiac ion channel blockers using ECG biomarkers and arrhythmia incidence in St. Kitts green monkeys (Chlorocebus Sabaeus)

2019 ◽  
Vol 99 ◽  
pp. 106595
Author(s):  
Bob Brockway ◽  
Shervin Liddie ◽  
David Moddrelle ◽  
Xavier Morton ◽  
Tom Delahanty ◽  
...  
Keyword(s):  
Ion Channel ◽  
Channel Blockers ◽  
Ion Channel Blockers ◽  
Green Monkeys

scholarly journals Synthesis and Pharmacological Evaluation ofN-(2,5-Disubstituted phenyl)-N‘-(3-substituted phenyl)-N‘-methylguanidines AsN-Methyl-d-aspartate Receptor Ion-Channel Blockers

1998 ◽  
Vol 41 (6) ◽  
pp. 1006-1006
Author(s):  
Lain-Yen Hu ◽  
Junqing Guo ◽  
Sharad S. Magar ◽  
James B. Fischer ◽  
Kathleen J. Burke-Howie ◽  
...  
Keyword(s):  
Ion Channel ◽  
Channel Blockers ◽  
Ion Channel Blockers ◽  
Pharmacological Evaluation ◽  
Aspartate Receptor
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