Hypoxia and re-oxygenation-induced EADs can be generated in the mouse heart model. 9-Phenanthrol abolished EADs, which strongly suggests the involvement of TRPM4 in the generation of EAD. This identifies non-selective cation channels inhibitors as new pharmacological candidates in the treatment of arrhythmias.

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Key pointsr The transient receptor potential melastatin 4 (TRPM4) inhibitor 9-phenanthrol reduces action potential duration in rabbit Purkinje fibres but not in ventricle.r TRPM4-like single channel activity is observed in isolated rabbit Purkinje cells but not in ventricular cells.r The TRPM4-like current develops during the notch and early repolarization phases of the action potential in Purkinje cells. Abstract Transient receptor potential melastatin 4 (TRPM4) Ca2+ -activated non-selective cation channel activity has been recorded in cardiomyocytes and sinus node cells from mammals. In addition, TRPM4 gene mutations are associated with human diseases of cardiac conduction, suggesting that TRPM4 plays a role in this aspect of cardiac function. Here we evaluate the TRPM4 contribution to cardiac electrophysiology of Purkinje fibres. Ventricular strips with Purkinje fibres were isolated from rabbit hearts. Intracellular microelectrodes recorded Purkinje fibre activity and the TRPM4 inhibitor 9-phenanthrol was applied to unmask potential TRPM4 contributions to the action potential. 9-Phenanthrol reduced action potential duration measured at the point of 50 and 90% repolarization with an EC 50 of 32.8 and 36.1×10−6 mol l −1 , respectively, but did not modulate ventricular action potentials. Inside-out patch-clamp recordings were used to monitor TRPM4 activity in isolated Purkinje cells. TRPM4-like single channel activity (conductance = 23.8 pS; equal permeability for Na + and K + ; sensitivity to voltage, Ca 2+ and 9-phenanthrol) was observed in 43% of patches from Purkinje cells but not from ventricular cells (0/16). Action potential clamp experiments performed in the whole-cell configuration revealed a transient inward 9-phenanthrol-sensitive current (peak density = −0.65 ± 0.15 pA pF -1 ; n = 5) during the plateau phases of the Purkinje fibre action potential. These results show that TRPM4 influences action potential characteristics in rabbit Purkinje fibres and thus could modulate cardiac conduction and be involved in triggering arrhythmias. Abbreviations 9-phe, 9-phenanthrol; AP, action potential; APA, Action potential amplitude; APD, action potential duration; APD x , action potential duration at x % of repolarization; I Ca , voltage-gated Ca 2+ current; I K1 , inward-rectifier K + current; I Ks , slow K + current; I Na , voltage-gated Na + current; I to , transient outward current; PC, Purkinje cell; PF, Purkinje fibre; RMP, resting membrane potential; TRPM4, transient receptor potential melastatin 4; V m , transmembrane potential; V max , maximum upstroke velocity of action potential during the depolarizing phase.

Argon has strong cardioprotective properties when applied in conditions of postconditioning and thus appears as a potential therapeutic tool in I/R situations.