Ryanodine‐receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long‐QT syndrome

Ryanodine‐receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in... 1INTRODUCTIONCellular calcium handling plays an important role in the origination of ventricular arrhythmias. Calcium overload is regarded as a major proarrhythmic factor in different entities of arrhythmias as it may lead to a prolongation of action potential duration and thereby induce early and delayed afterdepolarizations. Destabilization of the ryanodine receptor 2 (RYR2) closed state may increase the intracellular calcium level by releasing calcium from the sarcoplasmic reticulum. Activity of RYR2 is mediated by phosphorylation of the receptor and may be altered in structural heart disease leading to the origination of atrial and ventricular arrhythmias. Hyperphosphorylation of RYR2 induces an increased calcium release from the sarcoplasmic reticulum. The intracellular calcium concentration can be further augmented as a result of an increased activity of the sodium‐calcium‐exchanger (NCX). An association between a hyperphosphorylated ryanodine receptor and triggered activity has also been reported in long‐QT2 syndrome (LQT2).Dantrolene, an established drug for treatment of malignant hyperthermia, has been reported to target RYR2 and may thereby improve intracellular calcium handling in the setting of chronic heart failure. In single cell experiments, dantrolene reduced the calcium leak and increased the threshold for spontaneous release of calcium from the sarcoplasmic reticulum. In addition, dantrolene represents a promising http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Cardiovascular Electrophysiology Wiley

Ryanodine‐receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long‐QT syndrome