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

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. 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. 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. 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. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Citation

Na Li, Qiongling Wang, Martha Sibrian-Vazquez, Robert C Klipp, Julia O Reynolds, Tarah A Word, Larry Scott, Guy Salama, Robert M Strongin, Jonathan J Abramson, Xander H T Wehrens. Treatment of catecholaminergic polymorphic ventricular tachycardia in mice using novel RyR2-modifying drugs. International journal of cardiology. 2017 Jan 15;227:668-673

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PMID: 27838126

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