Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia in Mice Using Novel RyR2-Modifying Drugs

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International Journal of Cardiology

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Rationale Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal arrhythmic disorder caused by mutations in the type-2 ryanodine receptor (RyR2). Mutant RyR2 cause abnormal Ca2 + leak from the sarcoplasmic reticulum (SR), which is associated with the development of arrhythmias. Objective To determine whether derivatives of tetracaine, a local anesthetic drug with known RyR2 inhibiting action, could prevent CPVT induction by suppression of RyR2-mediated SR Ca2 + leak. Methods and results Confocal microscopy was used to assess the effects of tetracaine and 9 derivatives (EL1–EL9) on spontaneous Ca2 + sparks in ventricular myocytes isolated from RyR2-R176Q/+ mice with CPVT. Whereas each derivative suppressed the Ca2 + spark frequency, derivative EL9 was most effective at the screening dose of 500 nmol/L. At this high dose, the Ca2 + transient amplitude was not affected in myocytes from WT or R176Q/+ mice. The IC50 of EL9 was determined to be 13 nmol/L, which is about 400 × time lower than known RyR2 stabilizer K201. EL9 prevented the induction of ventricular tachycardia observed in placebo-treated R176Q/+ mice, without affecting heart rate or cardiac contractility. Conclusions Tetracaine derivatives represent a novel class of RyR2 stabilizing drugs that could be used for the treatment of the potentially fatal disorder catecholaminergic polymorphic ventricular tachycardia.



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