Cardiovascular Genetics Program, Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Ave, New York, NY 10016, USA.
Circ Res. 2011 Jul 22;109(3):291-5. doi: 10.1161/CIRCRESAHA.111.247338. Epub 2011 Jun 16.
Flecainide prevents arrhythmias in catecholaminergic polymorphic ventricular tachycardia, but the antiarrhythmic mechanism remains unresolved. It is possible for flecainide to directly affect the cardiac ryanodine receptor (RyR2); however, an extracellular site of action is suggested because of the hydrophilic nature of flecainide.
To investigate the mechanism for the antiarrhythmic action of flecainide in a RyR2(R4496C+/-) knock-in mouse model of catecholaminergic polymorphic ventricular tachycardia.
Flecainide prevented catecholamine-induced sustained ventricular tachycardia in RyR2(R4496C+/-) mice. Cellular studies were performed with isolated RyR2(R4496C+/-) myocytes. Isoproterenol caused the appearance of spontaneous Ca(2+) transients, which were unaffected by flecainide (6 μmol/L). Flecainide did not affect Ca(2+) transient amplitude, decay, or sarcoplasmic reticulum Ca(2+) content. Moreover, it did not affect the frequency of spontaneous Ca(2+) sparks in permeabilized myocytes. In contrast, flecainide effectively prevented triggered activity induced by isoproterenol. The threshold for action potential induction was increased significantly (P<0.01), which suggests a primary extracellular antiarrhythmic effect mediated by Na(+) channel blockade.
Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in RyR2(R4496C+/-) mice; however, at variance with previous reports, we observed minimal effects on intracellular Ca(2+) homeostasis. Our data suggest that the antiarrhythmic activity of the drug is caused by reduction of Na(+) channel availability and by an increase in the threshold for triggered activity.
氟卡尼可预防儿茶酚胺多形性室性心动过速中的心律失常，但抗心律失常机制仍未解决。氟卡尼可能直接影响心脏兰尼碱受体（RyR2）；然而，由于氟卡尼的亲水性，提示其作用部位在细胞外。
在儿茶酚胺多形性室性心动过速的 RyR2（R4496C+/-）基因敲入小鼠模型中研究氟卡尼的抗心律失常作用机制。
氟卡尼可预防 RyR2（R4496C+/-）小鼠儿茶酚胺诱导的持续性室性心动过速。用分离的 RyR2（R4496C+/-）肌细胞进行细胞研究。异丙肾上腺素引起自发性 Ca（2+）瞬变的出现，氟卡尼（6μmol/L）对其无影响。氟卡尼不影响 Ca（2+）瞬变幅度、衰减或肌浆网 Ca（2+）含量。此外，它不影响通透肌细胞中自发性 Ca（2+）火花的频率。相比之下，氟卡尼可有效预防异丙肾上腺素诱导的触发活动。动作电位诱导的阈值显著增加（P<0.01），这表明存在由 Na（+）通道阻断介导的主要细胞外抗心律失常作用。
氟卡尼可预防 RyR2（R4496C+/-）小鼠儿茶酚胺多形性室性心动过速；然而，与先前的报道不同，我们观察到细胞内 Ca（2+）稳态的影响最小。我们的数据表明，药物的抗心律失常活性是通过减少 Na（+）通道的可利用性和增加触发活动的阈值引起的。
