Mechanisms of flecainide induced negative inotropy: An in silico study

Yang, Pei; Giles, Wayne R.; Belardinelli, Luiz; Clancy, Colleen E.

doi:10.1016/j.yjmcc.2021.05.007

Cited by 4 publications

(3 citation statements)

References 69 publications

(121 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5) Although some of the existing class I antiarrhythmics have inhibitory effects on late I Na , 14) their potency is limited and, on the other hand, they often show unwanted cardio-suppressive effects through inhibitory effects on other ionic mechanisms such as the Ltype Ca 2+ channel current. 22,23) The present study showed that NCC-3902, a selective late I Na blocker, inhibited spontaneous firing of action potentials in the pulmonary vein myocardium, the main trigger of atrial fibrillation. Thus, selective late I Na blockers like NCC-3902 appear to be promising therapeutic agents for the treatment of atrial fibrillation.…”

Section: Discussionmentioning

confidence: 50%

“…This indicates that the negative inotropic effect of flecainide cannot be ascribed to late I Na blockade, but may be the result of other effects such as blockade of peak I Na , I Ca,L , I Kr , and the ryanodine receptor. 22,23) Thus, enhanced blocking selectivity towards late I Na appears to increase the safety margin between anti-fibrillatory activity and cardiosuppression.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibitory Effect of a Late Sodium Current Blocker, NCC-3902, on the Automaticity of the Guinea Pig Pulmonary Vein Myocardium

Namekata

Hiiro

Odaka

et al. 2022

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

The effect of blocking the persistent component of the sodium channel current (late I Na ) on the automatic activity of the isolated guinea pig pulmonary vein myocardium was examined. NCC-3902 blocked late I Na , but did not affect other major ion channel currents stably expressed in cell lines. In isolated pulmonary vein cardiomyocytes, NCC-3902 blocked the late I Na induced by a ramp depolarizing voltage clamp pulse similar to that of the pacemaker depolarization observed in the pulmonary vein myocardium. In isolated pulmonary vein tissue, NCC-3902 decreased the frequency of automatic firing of the myocardium through a reduction of the pacemaker depolarization slope. In isolated pulmonary vein cardiomyocytes, NCC-3902 significantly reduced the firing frequency of Ca 2 transients, but had no effect on Ca 2 sparks. NCC-3902 affected neither the spontaneous beating rate of the right atrium nor the contractile force of the ventricular myocardium. Selective blockers of late I Na like NCC-3902, which inhibit the automatic activity of the pulmonary vein myocardium, appear to be promising as drugs for the pharmacological treatment of atrial fibrillation.

show abstract

Section: Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of a Late Sodium Current Blocker, NCC-3902, on the Automaticity of the Guinea Pig Pulmonary Vein Myocardium

Namekata

Hiiro

Odaka

et al. 2022

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…Flecainide has a narrow therapeutic window between the effective dose and the dose that can produce adverse toxic effects. The target range for flecainide concentration is 0.5–2.4 μM in the clinical practice ( Melgari et al, 2015 ; Rabêlo Evangelista et al, 2021 ; Yang et al, 2021 ). Despite conflicting results in single-channel recordings, the therapeutic concentration of flecainide cannot block RyR2 effectively.…”

Section: Dissecting the Antiarrhythmic Mechanisms Of Flecainide In Cpvtmentioning

confidence: 99%

The Antiarrhythmic Mechanisms of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Peng

Lin

et al. 2022

Front. Physiol.

View full text Add to dashboard Cite

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe yet rare inherited arrhythmia disorder. The cornerstone of CPVT medical therapy is the use of β-blockers; 30% of patients with CPVT do not respond well to optimal β-blocker treatment. Studies have shown that flecainide effectively prevents life-threatening arrhythmias in CPVT. Flecainide is a class IC antiarrhythmic drug blocking cardiac sodium channels. RyR2 inhibition is proposed as the principal mechanism of antiarrhythmic action of flecainide in CPVT, while it is highly debated. In this article, we review the current progress of this issue.

show abstract