The transient receptor potential melastatin 4 channel inhibitor 9‐phenanthrol modulates cardiac sodium channel

Background and Purpose 9‐Phenanthrol, known as a specific inhibitor of the transient receptor potential melastatin 4 (TRMP4) channel, has been shown to modulate cardiac electrical activity and exert antiarrhythmic effects. However, its pharmacological effects remain to be fully explored. Here, we tested the hypothesis that cardiac sodium current inhibition contributes to the cardioprotective effect of 9‐phenanthrol. Experimental Approach Single ventricular myocytes (VMs) and Purkinje cells (PCs) were enzymatically isolated from rabbits. Arterially perfused rabbit wedge preparations were also used, and transmural electrocardiogram and endocardial action potentials (APs) were simultaneously recorded. Wild‐type and mutated human recombinant SCN5A were expressed in HEK293 cells. Anemonia toxin II (ATX‐II) was used to amplify the late sodium current (INaL) and induce arrhythmias. Whole‐cell patch clamp technique was used to record APs and ionic currents. Key Results 9‐Phenanthrol (10–50 μM) stabilized ventricular repolarization and abolished arrhythmias induced by ATX‐II in both isolated VMs, PCs and wedge preparations. Further study revealed that 9‐phenanthrol modulated the gating properties of cardiac sodium channels and dose‐dependently inhibited INaL and peak sodium current (INaP) in VMs with an IC50 of 18 and 71.5 μM respectively. Its ability to inhibit INaL was further confirmed in PCs and HEK293 cells expressing SCN5A mutations. Conclusions and Implications Our results indicate that 9‐phenanthrol modulates the gating properties of cardiac sodium channels and inhibits INaL and INaP, which may contribute to its antiarrhythmic and cardioprotective effects.