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Int J Cardiol. 2017 Jan 15;227:668-673. doi: 10.1016/j.ijcard.2016.10.078. Epub 2016 Oct 29.

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

Author information

1
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Physics, Portland State University, Portland, OR 97207, USA.
3
Department of Medicine, Heart and Vascular Institute, University of Pittsburgh, Pittsburg, PA 15260, USA.
4
Department of Chemistry, Portland State University, Portland, OR 97207, USA.
5
Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: wehrens@bcm.edu.

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.

KEYWORDS:

Calcium leak; Catecholaminergic polymorphic ventricular tachycardia; Sarcoplasmic reticulum; Tetracaine; Type-2 ryanodine receptor

PMID:
27838126
PMCID:
PMC5164850
DOI:
10.1016/j.ijcard.2016.10.078
[Indexed for MEDLINE]
Free PMC Article

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