A novel RyR2-selective stabilizer prevents stress-induced ventricular arrhythmias without impairing cardiac function
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Background and Purpose
Aberrant activation of the type 2 ryanodine receptor (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 harboring mutant RyR2s.
Experimental approach
In vitro effects of Ryanozole were evaluated by ER Ca 2+ -based assay and [ 3 H]Ryanodine binding assay using RyR2-expressing HEK293 cells. Two lines of mice with different arrhythmia severity, RyR2-R420W and -K4750Q, were employed for in vivo assessments. Intracellular Ca 2+ signals were analyzed in isolated cardiomyocytes using Cal520. Antiarrhythmic effects were evaluated by ECG under catecholaminergic challenge in anesthetized 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 similar IC 50 of 15−40 nM. The inhibition was more potent at lower cytosolic Ca 2+ concentrations. It 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 spontaneous arrhythmias during daily activity. Importantly, Ryanozole did not impair cardiac conduction or contractility, unlike conventional antiarrhythmic drugs.
Conclusions and implications
Ryanozole strongly suppresses RyR2 under diastolic Ca 2+ conditions, thereby preventing the arrhythmogenic trigger of aberrant Ca 2+ release. This mechanism likely provides potent antiarrhythmic effects while preserving cardiac function. Ryanozole is a promising therapeutic candidate treating RyR2-mediated arrhythmias, such as CPVT.
