Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs.

ABSTRACT

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 500nmol/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 13nmol/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.