In vitro detection of cardiotoxins or neurotoxins affecting ion channels or pumps using beating cardiomyocytes as alternative for animal testing

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Abstract

The present study investigated if and to what extent murine stem cell-derived beating cardiomyocytes within embryoid bodies can be used as a broad screening in vitro assay for neurotoxicity testing, replacing for example in vivo tests for marine neurotoxins. Effect of nine model compounds, acting on either the Na+, K+, or Ca2+ channels or the Na+/K+ ATP-ase pump, on the beating was assessed. Diphenhydramine, veratridine, isradipine, verapamil and ouabain induced specific beating arrests that were reversible and none of the concentrations tested induced cytotoxicity. Three K+ channel blockers, amiodarone, clofilium and sematilide, and the Na+/K+ ATPase pump inhibitor digoxin had no specific effect on the beating. In addition, two marine neurotoxins i.e. saxitoxin and tetrodotoxin elicited specific beating arrests in cardiomyocytes. Comparison of the results obtained with cardiomyocytes to those obtained with the neuroblastoma neuro-2a assay revealed that the cardiomyocytes were generally somewhat more sensitive for the model compounds affecting Na+ and Ca2+ channels, but less sensitive for the compounds affecting K+ channels. The stem cell-derived cardiomyocytes were not as sensitive as the neuroblastoma neuro-2a assay for saxitoxin and tetrodotoxin. It is concluded that the murine stem cell-derived beating cardiomyocytes provide a sensitive model for detection of specific neurotoxins and that the neuroblastoma neuro-2a assay may be a more promising cell-based assay for the screening of marine biotoxins
LanguageEnglish
Pages281-288
JournalToxicology in Vitro
Volume29
Issue number2
DOIs
Publication statusPublished - 2015

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Animal Testing Alternatives
Cardiotoxins
Ion Pumps
Neurotoxins
Ion Channels
Cardiac Myocytes
Assays
Animals
Stem cells
Saxitoxin
Testing
Neuroblastoma
Tetrodotoxin
Stem Cells
Screening
Pumps
Isradipine
Veratridine
Diphenhydramine
Amiodarone

Keywords

  • gated sodium-channels
  • membrane currents
  • calcium-channel
  • open-state
  • tetrodotoxin
  • toxins
  • cells
  • na+
  • diphenhydramine
  • inhibition

Cite this

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title = "In vitro detection of cardiotoxins or neurotoxins affecting ion channels or pumps using beating cardiomyocytes as alternative for animal testing",
abstract = "The present study investigated if and to what extent murine stem cell-derived beating cardiomyocytes within embryoid bodies can be used as a broad screening in vitro assay for neurotoxicity testing, replacing for example in vivo tests for marine neurotoxins. Effect of nine model compounds, acting on either the Na+, K+, or Ca2+ channels or the Na+/K+ ATP-ase pump, on the beating was assessed. Diphenhydramine, veratridine, isradipine, verapamil and ouabain induced specific beating arrests that were reversible and none of the concentrations tested induced cytotoxicity. Three K+ channel blockers, amiodarone, clofilium and sematilide, and the Na+/K+ ATPase pump inhibitor digoxin had no specific effect on the beating. In addition, two marine neurotoxins i.e. saxitoxin and tetrodotoxin elicited specific beating arrests in cardiomyocytes. Comparison of the results obtained with cardiomyocytes to those obtained with the neuroblastoma neuro-2a assay revealed that the cardiomyocytes were generally somewhat more sensitive for the model compounds affecting Na+ and Ca2+ channels, but less sensitive for the compounds affecting K+ channels. The stem cell-derived cardiomyocytes were not as sensitive as the neuroblastoma neuro-2a assay for saxitoxin and tetrodotoxin. It is concluded that the murine stem cell-derived beating cardiomyocytes provide a sensitive model for detection of specific neurotoxins and that the neuroblastoma neuro-2a assay may be a more promising cell-based assay for the screening of marine biotoxins",
keywords = "gated sodium-channels, membrane currents, calcium-channel, open-state, tetrodotoxin, toxins, cells, na+, diphenhydramine, inhibition",
author = "J.A.Y. Nicolas and P.J.M. Hendriksen and {de Haan}, L.H.J. and R. Koning and I.M.C.M. Rietjens and T.F.H. Bovee",
year = "2015",
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T1 - In vitro detection of cardiotoxins or neurotoxins affecting ion channels or pumps using beating cardiomyocytes as alternative for animal testing

AU - Nicolas, J.A.Y.

AU - Hendriksen, P.J.M.

AU - de Haan, L.H.J.

AU - Koning, R.

AU - Rietjens, I.M.C.M.

AU - Bovee, T.F.H.

PY - 2015

Y1 - 2015

N2 - The present study investigated if and to what extent murine stem cell-derived beating cardiomyocytes within embryoid bodies can be used as a broad screening in vitro assay for neurotoxicity testing, replacing for example in vivo tests for marine neurotoxins. Effect of nine model compounds, acting on either the Na+, K+, or Ca2+ channels or the Na+/K+ ATP-ase pump, on the beating was assessed. Diphenhydramine, veratridine, isradipine, verapamil and ouabain induced specific beating arrests that were reversible and none of the concentrations tested induced cytotoxicity. Three K+ channel blockers, amiodarone, clofilium and sematilide, and the Na+/K+ ATPase pump inhibitor digoxin had no specific effect on the beating. In addition, two marine neurotoxins i.e. saxitoxin and tetrodotoxin elicited specific beating arrests in cardiomyocytes. Comparison of the results obtained with cardiomyocytes to those obtained with the neuroblastoma neuro-2a assay revealed that the cardiomyocytes were generally somewhat more sensitive for the model compounds affecting Na+ and Ca2+ channels, but less sensitive for the compounds affecting K+ channels. The stem cell-derived cardiomyocytes were not as sensitive as the neuroblastoma neuro-2a assay for saxitoxin and tetrodotoxin. It is concluded that the murine stem cell-derived beating cardiomyocytes provide a sensitive model for detection of specific neurotoxins and that the neuroblastoma neuro-2a assay may be a more promising cell-based assay for the screening of marine biotoxins

AB - The present study investigated if and to what extent murine stem cell-derived beating cardiomyocytes within embryoid bodies can be used as a broad screening in vitro assay for neurotoxicity testing, replacing for example in vivo tests for marine neurotoxins. Effect of nine model compounds, acting on either the Na+, K+, or Ca2+ channels or the Na+/K+ ATP-ase pump, on the beating was assessed. Diphenhydramine, veratridine, isradipine, verapamil and ouabain induced specific beating arrests that were reversible and none of the concentrations tested induced cytotoxicity. Three K+ channel blockers, amiodarone, clofilium and sematilide, and the Na+/K+ ATPase pump inhibitor digoxin had no specific effect on the beating. In addition, two marine neurotoxins i.e. saxitoxin and tetrodotoxin elicited specific beating arrests in cardiomyocytes. Comparison of the results obtained with cardiomyocytes to those obtained with the neuroblastoma neuro-2a assay revealed that the cardiomyocytes were generally somewhat more sensitive for the model compounds affecting Na+ and Ca2+ channels, but less sensitive for the compounds affecting K+ channels. The stem cell-derived cardiomyocytes were not as sensitive as the neuroblastoma neuro-2a assay for saxitoxin and tetrodotoxin. It is concluded that the murine stem cell-derived beating cardiomyocytes provide a sensitive model for detection of specific neurotoxins and that the neuroblastoma neuro-2a assay may be a more promising cell-based assay for the screening of marine biotoxins

KW - gated sodium-channels

KW - membrane currents

KW - calcium-channel

KW - open-state

KW - tetrodotoxin

KW - toxins

KW - cells

KW - na+

KW - diphenhydramine

KW - inhibition

U2 - 10.1016/j.tiv.2014.11.010

DO - 10.1016/j.tiv.2014.11.010

M3 - Article

VL - 29

SP - 281

EP - 288

JO - Toxicology in Vitro

T2 - Toxicology in Vitro

JF - Toxicology in Vitro

SN - 0887-2333

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ER -