A novel RyR2-selective stabilizer prevents stress-induced ventricular tachycardia without compromising cardiac function
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Aims
Excessive activation of the type 2 ryanodine receptor (RyR2) causes lethal arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Stabilization of RyR2 in the closed state is expected to prevent the occurrence of these arrhythmias, but there are no clinically available antiarrhythmic drugs that are exclusively RyR2-specific. In this study, we investigated the antiarrhythmic effect of a high-affinity and selective RyR2 modulator, Ryanozole, using CPVT mouse models harboring mutant RyR2s.
Methods and Results
In vitro effects of Ryanozole were assessed by ER Ca 2+ -based assay using RyR2-expressing HEK293 cells and [ 3 H]Ryanodine binding assay. To evaluate in situ and in vivo effects of Ryanozole, we used two lines of mice, RyR2-R420W and -K4750Q, with different arrhythmia severity. Intracellular Ca 2+ signals were monitored with Cal520 in isolated ventricular cardiomyocytes. Antiarrhythmic effects of Ryanozole and three typical antiarrhythmic drugs were evaluated by electrocardiography (ECG) in anesthetized R420W and K4750Q mice challenged with catecholamine and in conscious K4750Q mice that showed activity-dependent arrhythmias. Cardiac function was assessed by echocardiography before and after drug administration. Ryanozole suppressed wild type and mutant RyR2s with 15−40 nM IC 50 . [ 3 H]Ryanodine binding showed that the inhibition was more potent at low [Ca 2+ ] cyt than at high [Ca 2+ ] cyt . In isolated cardiomyocytes, Ryanozole suppressed isoproterenol-induced Ca 2+ waves and sparks without affecting action potential-evoked Ca 2+ transients. Ryanozole effectively suppressed adrenaline-induced arrhythmias and terminated activity-dependent arrhythmias. Unlike conventional antiarrhythmic drugs, Ryanozole did neither affect ECG parameters nor impair cardiac contractility.
Conclusions
This study demonstrated that selective suppression of RyR2 alone is sufficient to prevent arrhythmias in CPVT without compromising cardiac function.
Translational perspective
Ryanozole is superior to conventional drugs in that it has potent antiarrhythmic effects without adverse effects such as cardiac contractile dysfunction and conduction delay. Ryanozole is a promising novel therapeutic candidate for the prevention and treatment of arrhythmias.
