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Cardiac arrhythmias can pose a major threat to a patient’s health and are difficult to treat. An import class of arrhythmias are related to a defective calcium homeostasis in the cardiomyocytes. This can occur during ischemia or can be caused by genetic mutations in the regulators of calcium homeostasis in cardiomyocytes. Extrasystolic increases in cytosolic calcium concentration lead to delayed afterdepolarizations (DADs) and triggered activity, resulting in the arrhythmias. Contributors to DADs are Ca2+-activated depolarizing currents. This group might include Transient Receptor Potential Melastatin 4 protein (TRPM4), a Ca2+-activated non-selective monovalent cation channel. Mutations in TRPM4 were previously associated with occurrence of familial conduction disorders, like Brugada syndrome and Progressive Familial Heart Block type 1 (PFHB1). Recent studies also found an increased and decreased susceptibility to cardiac arrhythmias in mice overexpressing TRPM4 and TRPM4-/- mice, respectively. These studies were bound to genetically modified mouse strains to study the physiological role of TRPM4 due to a lack of suitable in vivo inhibitors. Recently, meclofenamate has been discovered as a selective and potent inhibitor of TRPM4 in vitro. We aimed to investigate the role of TRPM4 in the development of cardiac arrhythmias via in vivo inhibition of TRPM4 with meclofenamate, and the potential of meclofenamate to prevent and suppress arrhythmias in freely moving mice. We induced arrhythmias with caffeine (75 mg/kg) in RyRR4496C/R4496C mice, an established disease model for catecholaminergic polymorphic ventricular tachycardia (CPVT). To test the role of TRPM4 in these events, we applied meclofenamate (30 mg/kg) before (pre-treatment) or after (post-treatment) administration of caffeine. Evaluation of meclofenamate’s effect on cardiac arrhythmias was performed by recording the ECG signals of freely moving mice via implanted telemetry devices (Data Sciences InternationalTM). The occurrence of ventricular arrhythmias (single ventricular ectopic beats (VEBs) and bidirectional ventricular tachycardia (biVT)) and conduction disturbances (CDs) was evaluated. We found that caffeine at a concentration of 75 mg/kg was an efficient inducer of cardiac arrhythmias in RyRR4496C/R4496C mice. We observed a dose-dependent effect of meclofenamate on the number of arrhythmic events. Both pre- and post-treatment with 30 mg/kg meclofenamate resulted in a substantial reduction of the amount of single VEBs and episodes and duration of biVT in RyRR4496C/R4496C mice. Post-treatment with meclofenamate elicited a stronger reducing effect on ventricular arrhythmias (near- complete suppression) than pre-treatment. We observed no apparent effect of meclofenamate on conduction disturbances in RyRR4496C/R4496C mice. Based on our results we can conclude that TRPM4 plays an important role in the development of ventricular arrhythmias. Meclofenamate at a concentration of 30 mg/kg proved to be a potent suppressor of ventricular arrhythmias in RyRR4496C/R4496C mice, which makes it an interesting compound in the research and development on new antiarrhythmic drugs. Furthermore, this model is suitable for in vivo studies on ventricular arrhythmias, but it appeared not to be efficient for research on conduction disturbances.