TRPM4 inhibition by meclofenamate suppresses Ca2+-dependent triggered arrhythmias

Abstract

Aims Cardiac arrhythmias are a major factor in the occurrence of morbidity and sudden death in patients with cardiovascular disease. Disturbances of Ca2+ homeostasis in the heart contribute to the initiation and maintenance of cardiac arrhythmias. Extrasystolic increases in intracellular Ca2+ lead to delayed afterdepolarizations and triggered activity, which can result in heart rhythm abnormalities. It is being suggested that the Ca2+-activated nonselective cation channel TRPM4 is involved in the aetiology of triggered activity, but the exact contribution and in vivo significance are still unclear. Methods and results In vitro electrophysiological and calcium imaging technique as well as in vivo intracardiac and telemetric electrocardiogram measurements in physiological and pathophysiological conditions were performed. In two distinct Ca2+-dependent proarrhythmic models, freely moving Trpm4−/− mice displayed a reduced burden of cardiac arrhythmias. Looking further into the specific contribution of TRPM4 to the cellular mechanism of arrhythmias, TRPM4 was found to contribute to a long-lasting Ca2+ overload-induced background current, thereby regulating cell excitability in Ca2+ overload conditions. To expand these results, a compound screening revealed meclofenamate as a potent antagonist of TRPM4. In line with the findings from Trpm4−/− mice, 10 µM meclofenamate inhibited the Ca2+ overload-induced background current in ventricular cardiomyocytes and 15 mg/kg meclofenamate suppressed catecholaminergic polymorphic ventricular tachycardia-associated arrhythmias in a TRPM4-dependent manner. Conclusion The presented data establish that TRPM4 represents a novel target in the prevention and treatment of Ca2+-dependent triggered arrhythmias.

Amino acid substitution in the S1 or CH1-CH2 linker domain of TRPM4: Two newTRPM4variants found in complete heart block patients lead to gain of expression and gain of current

“…However, in-vivo mouse studies did not find altered resting membrane potentials in Trpm4 KO mice (26), nor in AAV9-induced overexpression of WT Trpm4(27) . On the contrary, a recent study by Vandewiele et al used different pathological pro-arrhythmic mouse models to demonstrate that TRPM4 was partially responsible for a long-lasting inward background current induced by Ca 2+ -overload in cardiomyocytes (28) . Using Trpm4 KO mice or newly proposed TRPM4 inhibitor and the anti-inflammatory drug meclofenamate, these authors could suppress these arrhythmias without overt adverse effects.…”

TRPM4 Participates in Irradiation-Induced Aortic Valve Remodeling in Mice

“…Indeed, TRPM4 has a large distribution in tissues and contributes to numerous physiological processes including cardiac electrical activity [ 9 , 13 ]. At present, very few TRPM4 inhibitors are available and only two studies reported the effect of in vivo acute application of the TRPM4 inhibitors: one with 9-phenanthrol injected in rats which results in reduction in arterial pressure and heart rate [ 55 ]; another with meclofenamate injected in mice which results in QTc reduction on an ECG [ 56 ].…”

Transient receptor potential melastatin 4 (TRPM4) regulates hilar mossy cell loss in temporal lobe epilepsy

“…Furthermore, in epilepsy TRPM4 contributes to MC loss and increase seizure susceptibility. Our results are especially important in the light of recent findings identifying TRPM4 as a promising drug target in cardiac arrhythmias[39] especially because it has been shown that this type of arrhythmia is often associated with seizures[40]. Thus TRPM4 might be a common regulator of Ca 2+ dependent excitability both in cardiac myocytes and neurons.…”

“…target in cardiac arrhythmias [39] especially because it has been shown that this type of arrhythmia is often associated with seizures [40]. Thus TRPM4 might be a common regulator of Ca 2+ dependent excitability both in cardiac myocytes and neurons.…”