Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia in Mice Using Novel RyR2-Modifying DrugsInternational Journal of Cardiology
SponsorThis 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.].
AbstractRationale 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.
Locate the Document
Citation InformationLi, 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.