Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia in Mice Using Novel RyR2-Modifying Drugs
This work was supported by grants from the National Institutes of Health [R01-HL089598, R01-HL091947, R01-HL117641, R41-HL129570 to X.H.T.W., R56HL131649 to N.L., and R42-HL114206 to J.J.A.], and the American Heart Association [13EIA14560061 to X.H.T.W., and 14SDG20080008 to N.L.].
International Journal of Cardiology
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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Li, N., Wang, Q., Sibrian-Vazquez, M., Klipp, R. C., Reynolds, J. O., Word, T. A., ... & Wehrens, X. H. (2016). Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs. International Journal of Cardiology.