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The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments

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The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments. / Kohajda, Zsófia; Farkas-Morvay, Nikolett; Jost, Norbert; Nagy, Norbert; Geramipour, Amir; Horváth, András; Varga, Richárd S; Hornyik, Tibor; Corici, Claudia; Acsai, Károly; Horváth, Balázs; Prorok, János; Ördög, Balázs; Déri, Szilvia; Tóth, Dániel; Levijoki, Jouko; Pollesello, Piero; Koskelainen, Tuula; Otsomaa, Leena; Tóth, András; Baczkó, István; Leprán, István; Nánási, Péter P; Papp, Julius Gy; Varró, András; Virág, László.

In: PLOS ONE, Vol. 11, No. 11, 2016, p. e0166041.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Kohajda, Z, Farkas-Morvay, N, Jost, N, Nagy, N, Geramipour, A, Horváth, A, Varga, RS, Hornyik, T, Corici, C, Acsai, K, Horváth, B, Prorok, J, Ördög, B, Déri, S, Tóth, D, Levijoki, J, Pollesello, P, Koskelainen, T, Otsomaa, L, Tóth, A, Baczkó, I, Leprán, I, Nánási, PP, Papp, JG, Varró, A & Virág, L 2016, 'The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments', PLOS ONE, vol. 11, no. 11, pp. e0166041. https://doi.org/10.1371/journal.pone.0166041

APA

Kohajda, Z., Farkas-Morvay, N., Jost, N., Nagy, N., Geramipour, A., Horváth, A., Varga, R. S., Hornyik, T., Corici, C., Acsai, K., Horváth, B., Prorok, J., Ördög, B., Déri, S., Tóth, D., Levijoki, J., Pollesello, P., Koskelainen, T., Otsomaa, L., ... Virág, L. (2016). The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments. PLOS ONE, 11(11), e0166041. https://doi.org/10.1371/journal.pone.0166041

Vancouver

Kohajda Z, Farkas-Morvay N, Jost N, Nagy N, Geramipour A, Horváth A et al. The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments. PLOS ONE. 2016;11(11):e0166041. https://doi.org/10.1371/journal.pone.0166041

Bibtex

@article{7f80db53d3d34093a2c719e02b3ee6da,
title = "The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments",
abstract = "BACKGROUND: In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined.METHODS: Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 μg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts.RESULTS: ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 μM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 μM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts.CONCLUSIONS: The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.",
keywords = "Action Potentials, Animals, Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Calcium, Cells, Cultured, Dogs, Drug Discovery, Guinea Pigs, Heart Ventricles, Male, Myocytes, Cardiac, Rats, Sprague-Dawley, Sodium-Calcium Exchanger, Journal Article",
author = "Zs{\'o}fia Kohajda and Nikolett Farkas-Morvay and Norbert Jost and Norbert Nagy and Amir Geramipour and Andr{\'a}s Horv{\'a}th and Varga, {Rich{\'a}rd S} and Tibor Hornyik and Claudia Corici and K{\'a}roly Acsai and Bal{\'a}zs Horv{\'a}th and J{\'a}nos Prorok and Bal{\'a}zs {\"O}rd{\"o}g and Szilvia D{\'e}ri and D{\'a}niel T{\'o}th and Jouko Levijoki and Piero Pollesello and Tuula Koskelainen and Leena Otsomaa and Andr{\'a}s T{\'o}th and Istv{\'a}n Baczk{\'o} and Istv{\'a}n Lepr{\'a}n and N{\'a}n{\'a}si, {P{\'e}ter P} and Papp, {Julius Gy} and Andr{\'a}s Varr{\'o} and L{\'a}szl{\'o} Vir{\'a}g",
year = "2016",
doi = "10.1371/journal.pone.0166041",
language = "English",
volume = "11",
pages = "e0166041",
journal = "PLOS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

RIS

TY - JOUR

T1 - The Effect of a Novel Highly Selective Inhibitor of the Sodium/Calcium Exchanger (NCX) on Cardiac Arrhythmias in In Vitro and In Vivo Experiments

AU - Kohajda, Zsófia

AU - Farkas-Morvay, Nikolett

AU - Jost, Norbert

AU - Nagy, Norbert

AU - Geramipour, Amir

AU - Horváth, András

AU - Varga, Richárd S

AU - Hornyik, Tibor

AU - Corici, Claudia

AU - Acsai, Károly

AU - Horváth, Balázs

AU - Prorok, János

AU - Ördög, Balázs

AU - Déri, Szilvia

AU - Tóth, Dániel

AU - Levijoki, Jouko

AU - Pollesello, Piero

AU - Koskelainen, Tuula

AU - Otsomaa, Leena

AU - Tóth, András

AU - Baczkó, István

AU - Leprán, István

AU - Nánási, Péter P

AU - Papp, Julius Gy

AU - Varró, András

AU - Virág, László

PY - 2016

Y1 - 2016

N2 - BACKGROUND: In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined.METHODS: Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 μg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts.RESULTS: ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 μM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 μM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts.CONCLUSIONS: The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.

AB - BACKGROUND: In this study the effects of a new, highly selective sodium-calcium exchanger (NCX) inhibitor, ORM-10962 were investigated on cardiac NCX current, Ca2+ transients, cell shortening and in experimental arrhythmias. The level of selectivity of the novel inhibitor on several major transmembrane ion currents (L-type Ca2+ current, major repolarizing K+ currents, late Na+ current, Na+/K+ pump current) was also determined.METHODS: Ion currents in single dog ventricular cells (cardiac myocytes; CM), and action potentials in dog cardiac multicellular preparations were recorded utilizing the whole-cell patch clamp and standard microelectrode techniques, respectively. Ca2+ transients and cell shortening were measured in fluorescent dye loaded isolated dog myocytes. Antiarrhythmic effects of ORM-10962 were studied in anesthetized ouabain (10 μg/kg/min i.v.) pretreated guinea pigs and in ischemia-reperfusion models (I/R) of anesthetized coronary artery occluded rats and Langendorff perfused guinea pigs hearts.RESULTS: ORM-10962 significantly reduced the inward/outward NCX currents with estimated EC50 values of 55/67 nM, respectively. The compound, even at a high concentration of 1 μM, did not modify significantly the magnitude of ICaL in CMs, neither had any apparent influence on the inward rectifier, transient outward, the rapid and slow components of the delayed rectifier potassium currents, the late and peak sodium and Na+/K+ pump currents. NCX inhibition exerted moderate positive inotropic effect under normal condition, negative inotropy when reverse, and further positive inotropic effect when forward mode was facilitated. In dog Purkinje fibres 1 μM ORM-10962 decreased the amplitude of digoxin induced delayed afterdepolarizations (DADs). Pre-treatment with 0.3 mg/kg ORM-10962 (i.v.) 10 min before starting ouabain infusion significantly delayed the development and recurrence of ventricular extrasystoles (by about 50%) or ventricular tachycardia (by about 30%) in anesthetized guinea pigs. On the contrary, ORM-10962 pre-treatment had no apparent influence on the time of onset or the severity of I/R induced arrhythmias in anesthetized rats and in Langendorff perfused guinea-pig hearts.CONCLUSIONS: The present study provides strong evidence for a high efficacy and selectivity of the NCX-inhibitory effect of ORM-10962. Selective NCX inhibition can exert positive as well as negative inotropic effect depending on the actual operation mode of NCX. Selective NCX blockade may contribute to the prevention of DAD based arrhythmogenesis, in vivo, however, its effect on I/R induced arrhythmias is still uncertain.

KW - Action Potentials

KW - Animals

KW - Anti-Arrhythmia Agents

KW - Arrhythmias, Cardiac

KW - Calcium

KW - Cells, Cultured

KW - Dogs

KW - Drug Discovery

KW - Guinea Pigs

KW - Heart Ventricles

KW - Male

KW - Myocytes, Cardiac

KW - Rats, Sprague-Dawley

KW - Sodium-Calcium Exchanger

KW - Journal Article

U2 - 10.1371/journal.pone.0166041

DO - 10.1371/journal.pone.0166041

M3 - SCORING: Journal article

C2 - 27832106

VL - 11

SP - e0166041

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 11

ER -