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

• Published in: Canadian journal of physiology and pharmacology 2018-10, Vol.96 (10), p.1022-1029
• Main Authors: Veress, Roland, Baranyai, Dóra, Hegyi, Bence, Kistamás, Kornél, Dienes, Csaba, Magyar, János, Bányász, Tamás, Nánási, Péter P, Szentandrássy, Norbert, Horváth, Balázs
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Calcium - metabolism; Dogs; Female; Heart Ventricles - cytology; Male; Myocytes, Cardiac - cytology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Phenanthrenes - pharmacology; Potassium - metabolism; TRPM Cation Channels - antagonists & inhibitors
• ISSN: 0008-4212; 1205-7541
• DOI: 10.1139/cjpp-2018-0049

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 -dependent activation of TRPM4 channels. Transient outward (I ), rapid delayed rectifier (I ), and inward rectifier (I ) K currents were suppressed by 10 and 30 μM 9-phenanthrol with the blocking potency for I < I < I and partial reversibility. L-type Ca current was not affected up to the concentration of 30 μM. 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 μM), 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 μM 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.