丹曲林钠通过ryanodine 受体抑制作用，有效抑制长 QT 综合征的离体模型中的室性心律失常。

Ryanodine-receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long-QT syndrome.

机构信息

Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany.

Clinic of Exotic Pets, Reptiles, Exotic and Feral Birds, University of Hanover, Hanover, Germany.

出版信息

J Cardiovasc Electrophysiol. 2018 Mar;29(3):471-476. doi: 10.1111/jce.13412. Epub 2018 Jan 22.

DOI:10.1111/jce.13412

PMID:29314443

Abstract

AIMS

A significant antiarrhythmic potential of ryanodine receptor inhibition was reported in experimental studies. The aim of the present study was to assess potential antiarrhythmic effects of dantrolene in an experimental whole-heart model of drug-induced long-QT syndrome (LQTS).

METHODS

In 12 isolated rabbit hearts, long-QT-2-syndrome was simulated by infusion of erythromycin (300 μM). Twelve rabbit hearts were treated with veratridine (0.5 μM) to mimic long-QT-3-syndrome.

RESULTS

Monophasic action potentials and ECG showed a significant prolongation of QT-interval (+71 ms, P < 0.01) and action potential duration (APD, +43 ms, P < 0.01) after infusion of erythromycin as compared with baseline. Similar results were obtained in veratridine-treated hearts (QT-interval: +43 ms, P < 0.01; APD: +36 ms, P < 0.01). Both erythromycin (+36 ms, P < 0.05) and veratridine (+38 ms) significantly increased dispersion of repolarization. Additional infusion of dantrolene (20 μM) did not significantly alter QT-interval and APD but resulted in a significant reduction of dispersion of repolarization (erythromycin group: -33 ms, P < 0.05; veratridine group: -29 ms, P < 0.05). Lowering of potassium concentration resulted in the occurrence of early afterdepolarizations (EAD) and polymorphic ventricular tachycardia (VT) in 9 of 12 erythromycin-treated hearts (175 episodes) and 8 of 12 veratridine-treated hearts (66 episodes). Additional infusion of dantrolene significantly reduced occurrence of polymorphic VT and resulted in occurrence of EAD and polymorphic VT in 1 of 12 erythromycin-treated hearts (18 episodes) and 1 of 12 veratridine-treated hearts (3 episodes).

CONCLUSION

Inhibition of the ryanodine receptor by dantrolene significantly reduced occurrence of polymorphic VT in drug-induced LQTS. A significant reduction of spatial dispersion of repolarization represents a major antiarrhythmic mechanism. These results imply that dantrolene may represent a promising antiarrhythmic option in drug-induced LQTS.

摘要

目的

已有研究报道，兰尼碱受体抑制具有显著的抗心律失常作用。本研究旨在评估丹曲林钠在药物诱导长 QT 综合征（LQTS）的整体心脏实验模型中的潜在抗心律失常作用。

方法

在 12 个离体兔心中，通过输注红霉素（300μM）模拟长 QT-2 综合征。用藜芦碱（0.5μM）处理 12 个兔心以模拟长 QT-3 综合征。

结果

与基线相比，输注红霉素后单相动作电位和心电图显示 QT 间期显著延长（+71ms，P<0.01）和动作电位时程（APD，+43ms，P<0.01）。在藜芦碱处理的心脏中也得到了类似的结果（QT 间期：+43ms，P<0.01；APD：+36ms，P<0.01）。红霉素（+36ms，P<0.05）和藜芦碱（+38ms）均显著增加复极离散度。另外输注丹曲林钠（20μM）并未显著改变 QT 间期和 APD，但显著降低复极离散度（红霉素组：-33ms，P<0.05；藜芦碱组：-29ms，P<0.05）。降低钾浓度可导致 12 个红霉素处理的心脏中的 9 个（175 个发作）和 12 个藜芦碱处理的心脏中的 8 个（66 个发作）发生早期后除极（EAD）和多形性室性心动过速（VT）。另外输注丹曲林钠可显著减少多形性 VT 的发生，并导致 12 个红霉素处理的心脏中的 1 个（18 个发作）和 12 个藜芦碱处理的心脏中的 1 个（3 个发作）发生 EAD 和多形性 VT。