The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium-calcium exchanger inhibitor, GYKB-6635, in canine and guinea-pig hearts

Amir Geramipour, Zsófia Kohajda, Claudia Corici, János Prorok, Z. Szakonyi, Kinga Oravecz, Zoltán Márton, N. Nagy, A. Tóth, K. Acsai, L. Virág, A. Varró, N. Jost

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Abstract

The sodium-calcium exchanger (NCX) is considered as the major transmembrane transport mechanism that controls Ca2+ homeostasis. Its contribution to the cardiac repolarization has not yet been directly studied due to lack of specific inhibitors, so that an urgent need for more selective compounds. In this study, the electrophysiological effects of GYKB-6635, a novel NCX inhibitor, on the NCX, L-type calcium, and main repolarizing potassium currents as well as action potential (AP) parameters were investigated. Ion currents and AP recordings were investigated by applying the whole-cell patch clamp and standard microelectrode techniques in canine heart at 37 °C. Effects of GYKB-6635 were studied in ouabain-induced arrhythmias in isolated guinea-pig hearts. At a concentration of 1 µmol/L, GYKB significantly reduced both the inward and outward NCX currents (57% and 58%, respectively). Even at a high concentration (10 µmol/L), GYKB-6635 did not change the ICaL, the maximum rate of depolarization (dV/dtmax), the main repolarizing K+ currents, and the main AP parameters. GYKB-6635 pre-treatment significantly delayed the time to the development of ventricular fibrillation (by about 18%). It is concluded that GYKB-6635 is a potent and highly selective inhibitor of the cardiac NCX and, in addition, it is suggested to also contribute to the prevention of DAD-based arrhythmias.

Original languageEnglish
Pages (from-to)1090-1101
Number of pages12
JournalCanadian Journal of Physiology and Pharmacology
Volume94
Issue number10
DOIs
Publication statusPublished - Apr 12 2016

Fingerprint

Sodium-Calcium Exchanger
Action Potentials
Canidae
Guinea Pigs
Cardiac Arrhythmias
Microelectrodes
Ventricular Fibrillation
Ouabain
Potassium
Homeostasis
Ions
Calcium

Keywords

  • GYKB-6635
  • NCX
  • Ouabain-induced arrhythmias
  • Sodium-calcium exchanger

ASJC Scopus subject areas

  • Medicine(all)
  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

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title = "The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium-calcium exchanger inhibitor, GYKB-6635, in canine and guinea-pig hearts",
abstract = "The sodium-calcium exchanger (NCX) is considered as the major transmembrane transport mechanism that controls Ca2+ homeostasis. Its contribution to the cardiac repolarization has not yet been directly studied due to lack of specific inhibitors, so that an urgent need for more selective compounds. In this study, the electrophysiological effects of GYKB-6635, a novel NCX inhibitor, on the NCX, L-type calcium, and main repolarizing potassium currents as well as action potential (AP) parameters were investigated. Ion currents and AP recordings were investigated by applying the whole-cell patch clamp and standard microelectrode techniques in canine heart at 37 °C. Effects of GYKB-6635 were studied in ouabain-induced arrhythmias in isolated guinea-pig hearts. At a concentration of 1 µmol/L, GYKB significantly reduced both the inward and outward NCX currents (57{\%} and 58{\%}, respectively). Even at a high concentration (10 µmol/L), GYKB-6635 did not change the ICaL, the maximum rate of depolarization (dV/dtmax), the main repolarizing K+ currents, and the main AP parameters. GYKB-6635 pre-treatment significantly delayed the time to the development of ventricular fibrillation (by about 18{\%}). It is concluded that GYKB-6635 is a potent and highly selective inhibitor of the cardiac NCX and, in addition, it is suggested to also contribute to the prevention of DAD-based arrhythmias.",
keywords = "GYKB-6635, NCX, Ouabain-induced arrhythmias, Sodium-calcium exchanger",
author = "Amir Geramipour and Zs{\'o}fia Kohajda and Claudia Corici and J{\'a}nos Prorok and Z. Szakonyi and Kinga Oravecz and Zolt{\'a}n M{\'a}rton and N. Nagy and A. T{\'o}th and K. Acsai and L. Vir{\'a}g and A. Varr{\'o} and N. Jost",
year = "2016",
month = "4",
day = "12",
doi = "10.1139/cjpp-2015-0566",
language = "English",
volume = "94",
pages = "1090--1101",
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T1 - The investigation of the cellular electrophysiological and antiarrhythmic effects of a novel selective sodium-calcium exchanger inhibitor, GYKB-6635, in canine and guinea-pig hearts

AU - Geramipour, Amir

AU - Kohajda, Zsófia

AU - Corici, Claudia

AU - Prorok, János

AU - Szakonyi, Z.

AU - Oravecz, Kinga

AU - Márton, Zoltán

AU - Nagy, N.

AU - Tóth, A.

AU - Acsai, K.

AU - Virág, L.

AU - Varró, A.

AU - Jost, N.

PY - 2016/4/12

Y1 - 2016/4/12

N2 - The sodium-calcium exchanger (NCX) is considered as the major transmembrane transport mechanism that controls Ca2+ homeostasis. Its contribution to the cardiac repolarization has not yet been directly studied due to lack of specific inhibitors, so that an urgent need for more selective compounds. In this study, the electrophysiological effects of GYKB-6635, a novel NCX inhibitor, on the NCX, L-type calcium, and main repolarizing potassium currents as well as action potential (AP) parameters were investigated. Ion currents and AP recordings were investigated by applying the whole-cell patch clamp and standard microelectrode techniques in canine heart at 37 °C. Effects of GYKB-6635 were studied in ouabain-induced arrhythmias in isolated guinea-pig hearts. At a concentration of 1 µmol/L, GYKB significantly reduced both the inward and outward NCX currents (57% and 58%, respectively). Even at a high concentration (10 µmol/L), GYKB-6635 did not change the ICaL, the maximum rate of depolarization (dV/dtmax), the main repolarizing K+ currents, and the main AP parameters. GYKB-6635 pre-treatment significantly delayed the time to the development of ventricular fibrillation (by about 18%). It is concluded that GYKB-6635 is a potent and highly selective inhibitor of the cardiac NCX and, in addition, it is suggested to also contribute to the prevention of DAD-based arrhythmias.

AB - The sodium-calcium exchanger (NCX) is considered as the major transmembrane transport mechanism that controls Ca2+ homeostasis. Its contribution to the cardiac repolarization has not yet been directly studied due to lack of specific inhibitors, so that an urgent need for more selective compounds. In this study, the electrophysiological effects of GYKB-6635, a novel NCX inhibitor, on the NCX, L-type calcium, and main repolarizing potassium currents as well as action potential (AP) parameters were investigated. Ion currents and AP recordings were investigated by applying the whole-cell patch clamp and standard microelectrode techniques in canine heart at 37 °C. Effects of GYKB-6635 were studied in ouabain-induced arrhythmias in isolated guinea-pig hearts. At a concentration of 1 µmol/L, GYKB significantly reduced both the inward and outward NCX currents (57% and 58%, respectively). Even at a high concentration (10 µmol/L), GYKB-6635 did not change the ICaL, the maximum rate of depolarization (dV/dtmax), the main repolarizing K+ currents, and the main AP parameters. GYKB-6635 pre-treatment significantly delayed the time to the development of ventricular fibrillation (by about 18%). It is concluded that GYKB-6635 is a potent and highly selective inhibitor of the cardiac NCX and, in addition, it is suggested to also contribute to the prevention of DAD-based arrhythmias.

KW - GYKB-6635

KW - NCX

KW - Ouabain-induced arrhythmias

KW - Sodium-calcium exchanger

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