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

详细信息    查看全文

• 作者：Na Li^a ; ^b ; ¹ ; Qiongling Wang^a ; ^b ; ¹ ; Martha Sibrian-Vazquez^c ; ¹ ; Robert C. Klipp^c ; Julia O. Reynolds^a ; ^b ; Tarah A. Word^a ; ^b ; Larry Scott Jr.^a ; ^b ; Guy Salama^d ; Robert M. Strongin^e ; Jonathan J. Abramson^c ; Xander H.T. Wehrens^a ; ^b ; ^f ; ^g ; ^{wehrens@bcm.edu}
• 关键词：CPVT ; catecholaminergic polymorphic ventricular tachycardia ; RyR2 ; ryanodine receptor type-2 ; SCaWs ; spontaneous Ca2  ; + waves ; SR ; sarcoplasmic reticulum
• 刊名：International Journal of Cardiology
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：227
• 期：Complete
• 页码：668-673
• 全文大小：871 K
• 卷排序：227

文摘

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.ObjectiveTo 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 resultsConfocal 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.ConclusionsTetracaine 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.