美西律对不同心律失常模型的广谱抗心律失常作用。

Broad antiarrhythmic effect of mexiletine in different arrhythmia models.

机构信息

Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Albert-Schweitzer Campus 1, Münster, Germany.

出版信息

Europace. 2018 Aug 1;20(8):1375-1381. doi: 10.1093/europace/eux221.

DOI:10.1093/europace/eux221

PMID:29016765

Abstract

AIMS

Experimental studies and clinical reports suggest antiarrhythmic properties of mexiletine in different arrhythmias. We aimed at investigating mexiletine in experimental models of atrial fibrillation (AF) as well as in long-QT- (LQTS) and short-QT-syndrome (SQTS).

METHODS AND RESULTS

In 15 isolated rabbit hearts, erythromycin (300 µM) was infused for simulation of long-QT-2-syndrome. In further 13 hearts, veratridine was administered to simulate long-QT-3-syndrome. Both drugs induced a significant QT-prolongation (erythromycin: +87 ms, P < 0.01; veratridine: +19 ms, P < 0.05) and increased dispersion of repolarization (erythromycin: +55 ms, P < 0.01; veratridine +31 ms, P < 0.01). Additional infusion of mexiletine (25 µM) resulted in a significant reduction of dispersion (erythromycin: -43 ms, P < 0.01; veratridine: -26 ms, P < 0.05). Reproducible induction of torsade de pointes was observed in 13 of 15 erythromycin-treated hearts (192 episodes) and 6 of 13 veratridine-treated hearts (36 episodes). Additional infusion of mexiletine significantly reduced ventricular tachycardia (VT) incidence. With mexiletine, only 3 of 15 erythromycin-treated hearts (27 episodes) and 1 of 13 veratridine-treated hearts (2 episodes) presented polymorphic VT. In additional 9 hearts, the IK-ATP-channel-opener pinacidil was employed to simulate SQTS and significantly abbreviated ventricular repolarization (QT-interval: -18 ms, P < 0.05) and enhanced induction of ventricular fibrillation (VF). Mexiletine reversed the effects of pinacidil, increase refractory period (+127 ms, P < 0.01) and significantly suppressed induction of VF. In further 13 hearts AF was induced by combined treatment with acetylcholine/isoproterenol. Mexiletine also increased atrial refractory period (+80 ms, P < 0.01) and thereby effectively suppressed atrial fibrillation.

CONCLUSION

Acute infusion of mexiletine significantly reduced the occurrence of polymorphic VT in the presence of pharmacologically simulated LQTS. Furthermore, mexiletine demonstrated potent antiarrhythmic properties in a model of SQTS and in AF.

摘要

目的

实验研究和临床报告表明，美西律在不同类型心律失常中有抗心律失常作用。本研究旨在探讨美西律在心房颤动（AF）、长 QT （LQTS）和短 QT 综合征（SQTS）的实验模型中的作用。

方法和结果

在 15 个分离的兔心，用红霉素（300 μM）输注模拟长 QT-2 综合征。在另外 13 个心脏中，给予哇巴因以模拟长 QT-3 综合征。两种药物均导致 QT 间期显著延长（红霉素：+87 ms，P < 0.01；哇巴因：+19 ms，P < 0.05）和复极离散度增加（红霉素：+55 ms，P < 0.01；哇巴因：+31 ms，P < 0.01）。美西律（25 μM）的额外输注导致离散度显著降低（红霉素：-43 ms，P < 0.01；哇巴因：-26 ms，P < 0.05）。在 15 个红霉素处理的心脏中，有 13 个（192 个发作）和 13 个哇巴因处理的心脏中的 6 个（36 个发作）可重复诱导尖端扭转型室性心动过速（TdP）。美西律的额外输注显著降低了室性心动过速（VT）的发生率。用美西律治疗后，只有 15 个红霉素处理的心脏中的 3 个（27 个发作）和 13 个哇巴因处理的心脏中的 1 个（2 个发作）出现多形性 VT。在另外 9 个心脏中，使用 IK-ATP 通道开放剂吡那地尔模拟 SQTS，明显缩短心室复极（QT 间期：-18 ms，P < 0.05）并增强室颤（VF）的诱导。美西律逆转了吡那地尔的作用，增加了不应期（+127 ms，P < 0.01），并显著抑制了 VF 的诱导。在另外 13 个心脏中，乙酰胆碱/异丙肾上腺素联合处理诱导 AF。美西律也增加了心房不应期（+80 ms，P < 0.01），从而有效抑制心房颤动。