Selective inhibition of persistent sodium current by F 15845 prevents ischaemia‐induced arrhythmias

Pignier, Christophe; Rougier, Jean-Sébastien; Vié, Bruno; Culié, C; Verscheure, Y.; Vacher, Bernard; Abriel, Hugues; Grand, Bruno Le

doi:10.1111/j.1476-5381.2010.00884.x

Cited by 34 publications

(20 citation statements)

References 40 publications

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“…Unlike ranolazine [18] , 18β-GA produced a potent tonic block of I Na,L , which resulted in stronger anti-arrythmic effects. Recently, a more selective potent I Na,L blocker, F15845, also characterized by tonic blockade, has been demonstrated to be effective in preventing ischemia-induced arrhythmia [30] . HERG expresses I Kr , and blockage of HERG is believed to cause LQT, which can induce EAD and a Torsades de-Pointestype of ventricular arrhythmia, as observed after treatment …”

Section: Discussionmentioning

confidence: 99%

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

Xia

Zhao

et al. 2012

Acta Pharmacol Sin

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Aim:To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na + current, HERG and Kv1.5 channel currents. Methods: Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ∆KPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents. Results: Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1-100 μmol/L) blocked both the peak current (I Na,P ) and late current (I Na,L ) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked I Na,L (IC 50 =37.2±14.4 μmol/L) to I Na,P (IC 50 =100.4±11.2 μmol/L) generated by ∆KPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of I Na,P and 87% of I Na,L induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents. Conclusion: 18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels.

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Section: Discussionmentioning

confidence: 99%

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

Xia

Zhao

et al. 2012

Acta Pharmacol Sin

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“…Many local anesthetic and antiarrhythmic agents have greater potency to block I NaL than peak I Na (I NaP ). Certain compounds, such as ranolazine (Gupta et al, 2015) and F15845 (3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate) (Pignier et al, 2010), are described as preferential I NaL blockers.…”

Section: Introductionmentioning

confidence: 99%

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

2016

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GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)- [1,2,4]triazolo [4,3-a]pyridine (GS967) is a recently described, novel, sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current. However, there has been no reported systematic investigation of the effects of this compound on isolated sodium channels. Here, we examined the effects of GS967 on peak (I NaP ) and late (I NaL ) sodium current recorded from cells that heterologously expressed human cardiac voltage-gated sodium channel, the principle cardiac sodium channel. As previously described, we observed that GS967 exerted tonic block of I NaL (63%) to a significantly greater extent than I NaP (19%). However, GS967 also caused a reduction of I NaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evoked more potent UDB of I NaP (IC 50 5 0.07 mM) than ranolazine (16 mM) and lidocaine (17 mM). Use-dependent block was best explained by a significant slowing of recovery from fast and slow inactivation with a significant enhancement of slow inactivation in the presence of GS967. Furthermore, GS967 was found to exert these same effects on a prototypical long QT syndrome mutation (delKPQ). An engineered mutation at an interaction site for local anesthetic agents (F1760A) partially attenuated the effect of GS967 on UDB, but had no effect on tonic I NaL block. We conclude that GS967 is a preferential inhibitor of I NaL , but it also exerts previously unreported strong effects on slow inactivation and recovery from inactivation, resulting in substantial UDB that is not entirely dependent on a known interaction site for local anesthetic agents.

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“…In a very recent publication, a novel small molecule targeting multiple mechanisms involved in atrial fibrillation showed a 3-fold higher I Na, late inhibition over peak I Na inhibition, in addition to other ion channel blocking properties, and exhibited efficacy against AF in a chronic atrial tachypacing induced AF dog model [233]. Another novel I Na, late inhibitor, F 15845, reduced the incidence of coronary artery ligation induced arrhythmias in rats [234]. Based on these data, inhibition of I Na, late represents a promising approach for the treatment of both ventricular and atrial arrhythmias in HF.…”

Section: Na Late Inhibitorsmentioning

confidence: 99%

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

Baczkó

Leprán

Kiss

et al. 2014

CPD

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Heart failure (HF) is a clinical syndrome characterized by significant impairment of cardiac ventricular function. Atrial fibrillation (AF) is the most commonly observed sustained arrhythmia in clinical practice. Both HF and AF are associated with increased morbidity and mortality and their prevalence increases with age. Approximately 50% of patients with moderate HF die due to ventricular fibrillation that leads to sudden cardiac death. Patients with AF exhibit increased mortality due to HF and stroke. HF and AF often co-exist, and the development of the other condition further deteriorates prognosis. Both chronic HF and AF lead to structural and electrophysiological changes in the heart called remodeling, modifying therapeutic targets including those for antiarrhythmic intervention. Current pharmacological treatment of arrhythmias has major limitations due to low efficacy and serious adverse effects. In this review, the main aspects of electrical remodeling in HF and AF are discussed along with possible novel targets identified for future pharmacological antiarrhythmic therapy.Keywords: Heart failure, atrial fibrillation, cardiac arrhythmias, electrical remodeling, potassium channel expression, multi-channel blocking drugs. I. OVERVIEW AND CURRENT STATUS Epidemiology of Heart Failure, Atrial Fibrillation and their CombinationHeart failure (HF) is a clinical syndrome resulting from a wide range of cardiovascular disorders, featuring significant impairment of cardiac function that leads to reduced ventricular filling or ejection of blood. HF markedly reduces health-related quality of life [1], causes significant morbidity and high mortality and represents an enormous economic burden for the health care system [2]. The incidence of HF is increasing with age, with 20 per 1000 persons 65-69 years old and more than 80 per 1000 persons older than 85 [3] and its prevalence is increasing in a continuously aging population [2]. In spite of the significant advances in the treatment of HF, mortality rates remain poor at approximately 50% of patients dying within 5 years of diagnosis [4]. Serious ventricular arrhythmias are common in HF [5] and approximately 50% of HF patients die due to ventricular fibrillation leading to sudden cardiac death (SCD), the rate of which is several times higher in HF patients compared to the general population [6]. In addition to severe ventricular arrhythmias, atrial arrhythmias often develop in heart failure. Bradycardia can develop due to sinoatrial function impairment [7] that can exacerbate cardiac dysfunction [8], can lead to syncope and haemodynamic collapse and can be resolved by application of implantable devices [9].Atrial fibrillation (AF) is the most common sustained arrhythmia and it is associated with significant morbidity and mortality, especially due to the increased risk of heart failure and stroke [10][11][12]. The prevalence of AF increases with age, with 0.5% of patients affected in the 50 year old range, ~10% over the age of 80 [13] and the prediction is that it...

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Selective inhibition of persistent sodium current by F 15845 prevents ischaemia‐induced arrhythmias

Cited by 34 publications

References 40 publications

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

Future Perspectives in the Pharmacological Treatment of Atrial Fibrillation and Ventricular Arrhythmias in Heart Failure

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