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Pharmacological profile of the sodium current in human stem cell-derived cardiomyocytes compares to heterologous Nav1.5+β1 model

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Abstract
The cardiac Nav1.5 mediated sodium current (I-Na) generates the upstroke of the action potential in atrial and ventricular myocytes. Drugs that modulate this current can therefore be antiarrhythmic or proarrhythmic, which requires preclinical evaluation of their potential drug-induced inhibition or modulation of Nav1.5. Since Nav1.5 assembles with, and is modulated by, the auxiliary beta 1-subunit, this subunit can also affect the channel's pharmacological response. To investigate this, the effect of known Nav1.5 inhibitors was compared between COS-7 cells expressing Nav1.5 or Nav1.5+beta 1 using whole-cell voltage clamp experiments. For the open state class Ia blockers ajmaline and quinidine, and class Ic drug flecainide, the affinity did not differ between both models. For class Ib drugs phenytoin and lidocaine, which are inactivated state blockers, the affinity decreased more than a twofold when beta 1 was present. Thus, beta 1 did not influence the affinity for the class Ia and Ic compounds but it did so for the class Ib drugs. Human stem cell-derived cardiomyocytes (hSC-CMs) are a promising translational cell source for in vitro models that express a representative repertoire of channels and auxiliary proteins, including beta 1. Therefore, we subsequently evaluated the same drugs for their response on the I-Na in hSC-CMs. Consequently, it was expected and confirmed that the drug response of I-Na in hSC-CMs compares best to I-Na expressed by Nav1.5+beta 1.
Keywords
Pharmacology (medical), Pharmacology, arrhythmic, SCN5A, lidocaine, phenytoin, flecainide, quinidine, patch-clamp, CHANNEL ALPHA-SUBUNITS, CARDIAC NA+ CHANNEL, LIDOCAINE BLOCK, LOCAL-ANESTHETICS, HUMAN ATRIAL, BETA-1, RAT, COEXPRESSION, EXPRESSION, RECEPTOR

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MLA
Van de Sande, Dieter V., et al. “Pharmacological Profile of the Sodium Current in Human Stem Cell-Derived Cardiomyocytes Compares to Heterologous Nav1.5+β1 Model.” FRONTIERS IN PHARMACOLOGY, vol. 10, 2019, doi:10.3389/fphar.2019.01374.
APA
Van de Sande, D. V., Kopljar, I., Teisman, A., Gallacher, D. J., Snyders, D. J., Lu, H. R., & Labro, A. J. (2019). Pharmacological profile of the sodium current in human stem cell-derived cardiomyocytes compares to heterologous Nav1.5+β1 model. FRONTIERS IN PHARMACOLOGY, 10. https://doi.org/10.3389/fphar.2019.01374
Chicago author-date
Van de Sande, Dieter V., Ivan Kopljar, Ard Teisman, David J. Gallacher, Dirk J. Snyders, Hua Rong Lu, and Alain J Labro. 2019. “Pharmacological Profile of the Sodium Current in Human Stem Cell-Derived Cardiomyocytes Compares to Heterologous Nav1.5+β1 Model.” FRONTIERS IN PHARMACOLOGY 10. https://doi.org/10.3389/fphar.2019.01374.
Chicago author-date (all authors)
Van de Sande, Dieter V., Ivan Kopljar, Ard Teisman, David J. Gallacher, Dirk J. Snyders, Hua Rong Lu, and Alain J Labro. 2019. “Pharmacological Profile of the Sodium Current in Human Stem Cell-Derived Cardiomyocytes Compares to Heterologous Nav1.5+β1 Model.” FRONTIERS IN PHARMACOLOGY 10. doi:10.3389/fphar.2019.01374.
Vancouver
1.
Van de Sande DV, Kopljar I, Teisman A, Gallacher DJ, Snyders DJ, Lu HR, et al. Pharmacological profile of the sodium current in human stem cell-derived cardiomyocytes compares to heterologous Nav1.5+β1 model. FRONTIERS IN PHARMACOLOGY. 2019;10.
IEEE
[1]
D. V. Van de Sande et al., “Pharmacological profile of the sodium current in human stem cell-derived cardiomyocytes compares to heterologous Nav1.5+β1 model,” FRONTIERS IN PHARMACOLOGY, vol. 10, 2019.
@article{8704918,
  abstract     = {{The cardiac Nav1.5 mediated sodium current (I-Na) generates the upstroke of the action potential in atrial and ventricular myocytes. Drugs that modulate this current can therefore be antiarrhythmic or proarrhythmic, which requires preclinical evaluation of their potential drug-induced inhibition or modulation of Nav1.5. Since Nav1.5 assembles with, and is modulated by, the auxiliary beta 1-subunit, this subunit can also affect the channel's pharmacological response. To investigate this, the effect of known Nav1.5 inhibitors was compared between COS-7 cells expressing Nav1.5 or Nav1.5+beta 1 using whole-cell voltage clamp experiments. For the open state class Ia blockers ajmaline and quinidine, and class Ic drug flecainide, the affinity did not differ between both models. For class Ib drugs phenytoin and lidocaine, which are inactivated state blockers, the affinity decreased more than a twofold when beta 1 was present. Thus, beta 1 did not influence the affinity for the class Ia and Ic compounds but it did so for the class Ib drugs. Human stem cell-derived cardiomyocytes (hSC-CMs) are a promising translational cell source for in vitro models that express a representative repertoire of channels and auxiliary proteins, including beta 1. Therefore, we subsequently evaluated the same drugs for their response on the I-Na in hSC-CMs. Consequently, it was expected and confirmed that the drug response of I-Na in hSC-CMs compares best to I-Na expressed by Nav1.5+beta 1.}},
  articleno    = {{1374}},
  author       = {{Van de Sande, Dieter V. and Kopljar, Ivan and Teisman, Ard and Gallacher, David J. and Snyders, Dirk J. and Lu, Hua Rong and Labro, Alain J}},
  issn         = {{1663-9812}},
  journal      = {{FRONTIERS IN PHARMACOLOGY}},
  keywords     = {{Pharmacology (medical),Pharmacology,arrhythmic,SCN5A,lidocaine,phenytoin,flecainide,quinidine,patch-clamp,CHANNEL ALPHA-SUBUNITS,CARDIAC NA+ CHANNEL,LIDOCAINE BLOCK,LOCAL-ANESTHETICS,HUMAN ATRIAL,BETA-1,RAT,COEXPRESSION,EXPRESSION,RECEPTOR}},
  language     = {{eng}},
  pages        = {{12}},
  title        = {{Pharmacological profile of the sodium current in human stem cell-derived cardiomyocytes compares to heterologous Nav1.5+β1 model}},
  url          = {{http://dx.doi.org/10.3389/fphar.2019.01374}},
  volume       = {{10}},
  year         = {{2019}},
}

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