REAL

Transient receptor potential melastatin 4 channel inhibitor 9-phenanthrol inhibits K(+) but not Ca(2+) currents in canine ventricular myocytes

Veress, Roland and Baranyai, Dóra and Hegyi, B. and Kistamás, Kornél and Dienes, C. and Magyar, János and Bányász, Tamás and Nánási, Péter Pál and Szentandrássy, Norbert and Horváth, Balázs (2018) Transient receptor potential melastatin 4 channel inhibitor 9-phenanthrol inhibits K(+) but not Ca(2+) currents in canine ventricular myocytes. CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY, 96 (10). pp. 1022-1029. ISSN 0008-4212

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Abstract

The role of transient receptor potential melastatin 4 (TRPM4) channels has been frequently tested using their inhibitor 9-phenanthrol in various cardiac preparations; however, the selectivity of the compound is uncertain. Therefore, in the present study, the concentration-dependent effects of 9-phenanthrol on major ionic currents were studied in canine isolated ventricular cells using whole-cell configuration of the patch-clamp technique and 10 mM BAPTA-containing pipette solution to prevent the Ca(2+)-dependent activation of TRPM4 channels. Transient outward (Ito1), rapid delayed rectifier (IKr), and inward rectifier (IK1) K(+) currents were suppressed by 10 and 30 muM 9-phenanthrol with the blocking potency for IK1 < IKr < Ito1 and partial reversibility. L-type Ca(2+) current was not affected up to the concentration of 30 muM. In addition, a steady outward current was detected at voltages positive to -40 mV in 9-phenanthrol, which was larger at more positive voltages and larger 9-phenanthrol concentrations. Action potentials were recorded using microelectrodes. Maximal rate of depolarization, phase-1 repolarization, and terminal repolarization were decreased and the plateau potential was depressed by 9-phenanthrol (3-30 muM), congruently with the observed alterations of ionic currents. Significant action potential prolongation was observed by 9-phenanthrol in the majority of the studied cells, but only at 30 muM concentration. In conclusion, 9-phenanthrol is not selective to TRPM4 channels in canine ventricular myocardium; therefore, its application as a TRPM4 blocker can be appropriate only in expression systems but not in native cardiac cells.

Item Type: Article
Additional Information: Funding Agency and Grant Number: National Research Development and Innovation Office [NKFIH-K115397, NKFIH-K109736, NKFIH-PD120794]; European Union [GINOP-2.3.2.-15-2016-00040, EFOP-3.6.2-16-2017-00006]; European Regional Development Fund; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry of Human Capacities [UNKP-17-4-III-DE-201]; University of Debrecen [RH/751/2015]; Faculty of Dentistry, University of Debrecen\n Funding text: This work was funded by the National Research Development and Innovation Office (NKFIH-K115397, NKFIH-K109736, and NKFIH-PD120794). Further support was obtained from GINOP-2.3.2.-15-2016-00040 and EFOP-3.6.2-16-2017-00006 projects, which are co-financed by the European Union and the European Regional Development Fund. The work was also supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences to B. Horvath; by the UNKP-17-4-III-DE-201 New National Excellence Program of the Ministry of Human Capacities to B. Horvath; and by the University of Debrecen (RH/751/2015) to N. Szentandrassy, who gratefully acknowledges the financial support for young scientists by the Faculty of Dentistry, University of Debrecen. The authors thank Eva Sagi for excellent technical assistance.\n Funding Agency and Grant Number: National Research Development and Innovation Office [NKFIH-K115397, NKFIH-K109736, NKFIH-PD120794]; European Union [GINOP-2.3.2.-15-2016-00040, EFOP-3.6.2-16-2017-00006]; European Regional Development Fund; Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences; New National Excellence Program of the Ministry of Human Capacities [UNKP-17-4-III-DE-201]; University of Debrecen [RH/751/2015]; Faculty of Dentistry, University of Debrecen Funding text: This work was funded by the National Research Development and Innovation Office (NKFIH-K115397, NKFIH-K109736, and NKFIH-PD120794). Further support was obtained from GINOP-2.3.2.-15-2016-00040 and EFOP-3.6.2-16-2017-00006 projects, which are co-financed by the European Union and the European Regional Development Fund. The work was also supported by the Janos Bolyai Research Scholarship of the Hungarian Academy of Sciences to B. Horvath; by the UNKP-17-4-III-DE-201 New National Excellence Program of the Ministry of Human Capacities to B. Horvath; and by the University of Debrecen (RH/751/2015) to N. Szentandrassy, who gratefully acknowledges the financial support for young scientists by the Faculty of Dentistry, University of Debrecen. The authors thank Eva Sagi for excellent technical assistance.
Uncontrolled Keywords: MYOCARDIUM; ION CHANNELS; CARDIOMYOCYTES; BLOCK; Pharmacology & Pharmacy; 9-phenanthrol; TRPM4 channels; cardiac ionic currents; cardiac action potentials; NONSELECTIVE CATION CHANNEL; TRPM4;
Subjects: R Medicine / orvostudomány > RM Therapeutics. Pharmacology / terápia, gyógyszertan
SWORD Depositor: MTMT SWORD
Depositing User: MTMT SWORD
Date Deposited: 23 Sep 2019 15:58
Last Modified: 23 Sep 2019 15:58
URI: http://real.mtak.hu/id/eprint/100563

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