Journal
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
Volume 96, Issue 10, Pages 1022-1029Publisher
CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS
DOI: 10.1139/cjpp-2018-0049
Keywords
9-phenanthrol; TRPM4 channels; cardiac ionic currents; cardiac action potentials; canine myocytes
Categories
Funding
- 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
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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 Ca2+-dependent activation of TRPM4 channels. Transient outward (I-to1), rapid delayed rectifier (I-Kr), and inward rectifier (I-K1) K+ currents were suppressed by 10 and 30 mu M 9-phenanthrol with the blocking potency for I-K1 < I-Kr < I-to1 and partial reversibility. L-type Ca2+ current was not affected up to the concentration of 30 mu M. 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 mu M), 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 mu M 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.
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