0222: The TRPM4 channel modulates mammalian sinus rhythm

BackgroundThe transient receptor potential melastatin 4 (TRPM4) channel produces a Ca2+-activated non-selective monovalent cationic current that was detected in several cardiac preparations, including mouse sino atrial node isolated cells. TRPM4 is known to participate in spontaneous electrical activities such as in neurons or in cardiac ventricular preparations submitted to hypoxia/reoxygenation. Here, we evaluated whether it is involved in sinus rhythm.MethodsWe used mouse, rat and rabbit isolated right atria that exhibited spontaneous beating since they contained the sinus node. Intracellular microelectrodes were used to record the spontaneous action potentials under superfusion of oxygenated physiological solution.ResultsIn mouse, superfusion of the non-selective cation channel inhibitor flufenamic acid significantly reduced spontaneous beating rate to 89±2% (n=8) and 38±9% (n=4) of control for 10-5 and 10-4 mol.L-1 respectively. Moreover, superfusion of the TRPM4 specific inhibitor 9-phenanthrol produced a concentration-dependant reduction in AP rate (maximal reduction = 62±3% that of control; EC50=8x10-6 mol.L-1 for 9-phenanthrol; n=13) in wild type mice, but not in Trpm4-/- mice. Interestingly, the effect of 9-phenanthrol was higher when then initial beating rate was low. Similar results were obtained in rat and rabbit. Recording the activity of specific sinoatrial node cells in rabbit revealed that 10-5 mol.L-1 9-phenanthrol reduced diastolic depolarization slope by 22±4% (n=4).ConclusionIt is know that the diastolic depolarization slope is due to the funny current If, the Na/Ca exchanger, the T-type Ca2+ current, and modestly, a Ca2+-activated non-selective cationic current. TRPM4 most likely participates in this last current, exerting an effect against bradycardia