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.
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors: Amir
authors: A
authors: Geramipour
authors: b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.
authors: Zsófia
authors: Z
authors: Kohajda
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors: Claudia
authors: C
authors: Corici
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors: János
authors: J
authors: Prorok
authors: c Institute of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Szeged, H-6720 Szeged, Hungary.
authors: Zsolt
authors: Z
authors: Szakonyi
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors: Kinga
authors: K
authors: Oravecz
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.
authors: Zoltán
authors: Z
authors: Márton
authors: b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.
authors: Norbert
authors: N
authors: Nagy
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.|b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.
authors: András
authors: A
authors: Tóth
authors: b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.
authors: Károly
authors: K
authors: Acsai
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.|b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.
authors: László
authors: L
authors: Virág
authors: a Department of Pharmacology & Pharmacotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary.|b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.
authors: András
authors: A
authors: Varró
authors: b MTA-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary.|d "Victor Babes" University of Medicine and Pharmacy, Timisoara, Romania.
authors: Norbert
authors: N
authors: Jost
keywords: GYKB-6635; NCX; arythmies provoquées par l’ouabaïne; ouabain-induced arrhythmias; sodium–calcium exchanger; échangeur sodium–calcium