A novel selective stabilizer of the ryanodine receptor 2 prevents stress‐induced ventricular arrhythmias without impairing cardiac function

Abstract Background and Purpose Aberrant activation of type 2 ryanodine receptors (RyR2) causes lethal arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Developing drugs that suppress RyR2 hyperactivation may be key to novel arrhythmia treatments. This study evaluated the antiarrhythmic potential of Ryanozole, a recently developed novel RyR2 modulator with high affinity and selectivity, using CPVT mouse models harbouring mutant RyR2s. Experimental Approach In vitro effects of Ryanozole were evaluated by endoplasmic reticulum (ER) Ca 2+ ‐based assay and [ 3 H]ryanodine‐binding assay using RyR2‐expressing HEK293 cells. Two lines of mice with different arrhythmia severities, RyR2‐R420W and RyR2‐K4750Q, were employed for in vivo and ex vivo assessments. Intracellular Ca 2+ signals were analysed in isolated cardiomyocytes using Cal‐520. Antiarrhythmic effects were evaluated by electrocardiography (ECG) under catecholaminergic challenge in anaesthetized mice and during spontaneous arrhythmias in conscious mice. ECG and echocardiographic parameters were evaluated before and after drug administration. Key Results Ryanozole inhibited both wild‐type and mutant RyR2s with an IC 50 of 15–40 nM. Inhibition was more potent at lower cytosolic Ca 2+ concentrations. Ryanozole suppressed Ca 2+ waves and Ca 2+ sparks without affecting action potential‐evoked Ca 2+ transients. Ryanozole effectively prevented adrenaline‐induced arrhythmias and rapidly terminated ongoing spontaneous arrhythmias during daily activity. Importantly, Ryanozole did not impair cardiac conduction or contractility, unlike conventional antiarrhythmic drugs. Conclusion and Implications Ryanozole preferentially suppresses RyR2 under diastolic Ca 2+ conditions, thereby preventing the arrhythmogenic trigger of aberrant Ca 2+ release. This mechanism may provide potent antiarrhythmic effects while preserving cardiac function. Ryanozole is a potential therapeutic candidate for RyR2‐mediated arrhythmias, such as CPVT.