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Persistent sodium current (INaP) is an important activity-dependent regulator of neuronal excitability. It is involved in a variety of physiological and pathological processes, including pacemaking, prolongation of sensory potentials, neuronal injury, chronic pain and diseases such as epilepsy and amyotrophic lateral sclerosis. Despite its importance, neither the molecular basis nor the regulation of INaP are sufficiently understood. Of particular significance is a solid knowledge and widely accepted consensus about pharmacological tools for analysing the function of INaP and for developing new therapeutic strategies. However, the literature on INaP is heterogeneous, with varying definitions and methodologies used across studies. To address these issues, we provide a systematic review of the current state of knowledge on INaP, with focus on mechanisms and effects of this current in the central nervous system. We provide an overview of the specificity and efficacy of the most widely used INaP blockers: amiodarone, cannabidiol, carbamazepine, cenobamate, eslicarbazepine, ethosuximide, gabapentin, GS967, lacosamide, lamotrigine, lidocaine, NBI-921352, oxcarbazepine, phenytoine, PRAX-562, propofol, ranolazine, riluzole, rufinamide, topiramate, valproaic acid and zonisamide. We conclude that there is strong variance in the pharmacological effects of these drugs, and in the available information. At present, GS967 and riluzole can be regarded bona fide INaP blockers, while phenytoin and lacosamide are blockers that only act on the slowly inactivating component of sodium currents.

In the late ’90, Dr. Indira Raman, at the time a postdoctoral fellow with Dr. Bruce Bean, at Harvard University, identified a new type of sodium current, flowing through the channels that reopens when the membrane is repolarized. This current, called “resurgent Sodium current,” was originally identified in cerebellar Purkinje neurons and has now been confirmed in around 20 different neuronal types. Since moving to Northwestern University in 1999 to establish her own research group, Dr. Raman has dedicated great efforts in identifying the mechanisms supporting the resurgent Sodium current and how its biophysical properties shape the firing of the different cell types. Her work has impacted greatly the field of cellular neurophysiology, from basic research to translation neuroscience. In fact, alterations in the resurgent sodium currents have been observed in several neuropathologies, from Huntington’s disease to epilepsy. In this Perspective we will focus on the current knowledge on the expression and function of the resurgent Sodium current in neurons of the cerebral cortex and hippocampus. We will also briefly highlight the role of Dr. Raman’s as teacher and mentor, not only for her pupils, but for the whole scientific community.

Background Safinamide (SAF), an α-aminoamide derivative and a selective, reversible monoamine oxidase (MAO)-B inhibitor, has both dopaminergic and nondopaminergic (glutamatergic) properties. Several studies have explored the potential of SAF against various neurological disorders; however, to what extent SAF modulates the magnitude, gating, and voltage-dependent hysteresis [Hys (V) ] of ionic currents remains unknown. Methods With the aid of patch-clamp technology, we investigated the effects of SAF on voltage-gated sodium ion (Na V ) channels in pituitary GH3 cells. Results SAF concentration-dependently stimulated the transient (peak) and late (sustained) components of voltage-gated sodium ion current ( I Na ) in pituitary GH 3 cells. The conductance–voltage relationship of transient I Na [ I Na(T) ] was shifted to more negative potentials with the SAF presence; however, the steady-state inactivation curve of I Na(T) was shifted in a rightward direction in its existence. SAF increased the decaying time constant of I Na(T) induced by a train of depolarizing stimuli. Notably, subsequent addition of ranolazine or mirogabalin reversed the SAF-induced increase in the decaying time constant. SAF also increased the magnitude of window I Na induced by an ascending ramp voltage V ramp . Furthermore, SAF enhanced the Hys (V) behavior of persistent I Na induced by an upright isosceles-triangular V ramp . Single-channel cell-attached recordings indicated SAF effectively increased the open-state probability of Na V channels. Molecular docking revealed SAF interacts with both MAO and Na V channels. Conclusion SAF may interact directly with Na V channels in pituitary neuroendocrine cells, modulating membrane excitability.

Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ([Na+]i) and calcium ([Ca2+]i) concentration homeostasis of myocardial cells. A decreased efflux or increased influx of sodium may cause cellular sodium overload. Sodium overload is followed by an increased influx of calcium through sodium-calcium exchange. Failure to maintain the homeostasis of [Na+]i and [Ca2+]i leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (sodium channels, exchangers and transporters) to the rise in [Na+]i remain a matter of debate. Nevertheless, both the sodium-hydrogen exchanger and abnormal sodium channel conductance (that is, increased late sodium current (INa)) are likely to contribute to the rise in [Na+]i. The focus of this review is on the role of the late (sustained/persistent) INa in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late INa, reduces [Na+]i-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late INa can reduce [Na+]i-dependent calcium overload and its detrimental effects on myocardial function.

Barbaloin (10-β- D -glucopyranosyl-1,8-dihydroxy-3-(hydroxymethyl)-9(10H)-anthracenone) is extracted from the aloe plant and has been reported to have anti-inflammatory, antitumor, antibacterial, and other biological activities. Here, we investigated the effects of barbaloin on cardiac electrophysiology, which has not been reported thus far. Cardiac action potentials (APs) and ionic currents were recorded in isolated rabbit ventricular myocytes using whole-cell patch-clamp technique. Additionally, the antiarrhythmic effect of barbaloin was examined in Langendorff-perfused rabbit hearts. In current-clamp recording, application of barbaloin (100 and 200 μmol/L) dose-dependently reduced the action potential duration (APD) and the maximum depolarization velocity (Vmax), and attenuated APD reverse-rate dependence (RRD) in ventricular myocytes. Furthermore, barbaloin (100 and 200 μmol/L) effectively eliminated ATX II-induced early afterdepolarizations (EADs) and Ca 2+ -induced delayed afterdepolarizations (DADs) in ventricular myocytes. In voltage-clamp recording, barbaloin (10–200 μmol/L) dose-dependently inhibited L-type calcium current ( I Ca.L ) and peak sodium current ( I Na.P ) with IC 50 values of 137.06 and 559.80 μmol/L, respectively. Application of barbaloin (100, 200 μmol/L) decreased ATX II-enhanced late sodium current ( I Na.L ) by 36.6%±3.3% and 71.8%±6.5%, respectively. However, barbaloin up to 800 μmol/L did not affect the inward rectifier potassium current ( I K1 ) or the rapidly activated delayed rectifier potassium current ( I Kr ) in ventricular myocytes. In Langendorff-perfused rabbit hearts, barbaloin (200 μmol/L) significantly inhibited aconitine-induced ventricular arrhythmias. These results demonstrate that barbaloin has potential as an antiarrhythmic drug.

Late sodium current in cardiac cells is very small compared with the fast component, but as it flows throughout the action potential it may make a substantial contribution to sodium loading during each cardiac cycle. Late sodium current may contribute to triggering arrhythmia in two ways: by causing repolarisation failure (early afterdepolarisations); and by triggering late afterdepolarisations attributable to calcium oscillations in sodium–calcium overload conditions. Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as ischaemia in which sodium–calcium overload is a major feature.

BackgroundSodium-glucose cotransporter 2 (SGLT2) inhibitors, an effective treatment for diabetes, have recently shown significant cardiac protective properties including a potential reduction in arrhythmias. The direct effects of SGLT2 inhibitors on cardiac electrophysiology remain unclear. Understanding the impact of SGLT2 inhibitors could offer invaluable insights for patients at risk of arrhythmias.MethodsWhole cell patch clamping was performed on human embryonic kidney (HEK) cells expressing Nav1.5. Cells were incubated with SGLT2 inhibitor dapagliflozin (0.1 to 10µM) for four hours, or with Dimethylsulfoxide (DMSO) as a control. Following incubation, the cardiac voltage-gated sodium current (INa) was measured. To assess effects of SGLT2 inhibitors on the whole heart electrophysiology, optical mapping was performed in the intact mouse heart loaded with potentiometric dye Di-4-ANEPPS. Hearts were recorded at baseline and following treatment with 10µM dapagliflozin, and data analysed using ElectroMap.ResultsWhen measured from a holding potential of -100 mV Dapagliflozin increased peak sodium current density. Dapagliflozin led to a more negative V50,act, compared to control (See table 1). Neither concentration of Dapagliflozin altered reversal potential (See table 1). Dapagliflozin also delayed peak INa time dependent recovery (See table 1). At a holding potential of -120 mV, Dapagliflozin increased peak INa when compared to control (-205.9± 34.68pA/pF, -208.7± 38.80 pA/pF, -235.4± 34.54 pA/pF, and -125.9 ± 19.02 pA/pF for 10uM, 1uM, 0.1uM Dapagliflozin and DMSO group respectively, p<0.05, figure 2B). However, Dapagliflozin had no effects at more physiologically relevant holding potential of -90 to-60 mV (See figure 2).Ongoing experiments are examining the effects of Dapagliflozin on INa in cardiomyocytes derived from induced pluripotent stem cells, and epicardial action potentials in the hearts of healthy mice using cardiac optical mapping.ConclusionOur findings indicate that whilst Dapagliflozin does alter biophysical properties of fast voltage gated sodium channels, these are unlikely to alter the depolarisation and conduction in a healthy myocardium, at physiological resting membrane potentials.Abstract BS52 Figure 1SGLT2 inhibitors changed peak sodium currents of HEK cells expressing sodium 1.5 channels. A) Current density-voltage relationships of the peak sodium channels in four different HEKNav1.5. cells: incubated with SGLT2 inhibitors (10μM, 1μM, 0.1μM) or incubated with 0.01% DMSO (control) for 4 hours, using the protocol shown inside. B) Maximum peak sodium current density in HEKNav1.5. cells with or without SGLT2 inhibitors. Each bar shows the mean±SEM of n=10 experiments in each group, and each point represents one experiment. *** p< <0.0001 vs. controlAbstract BS52 Figure 2The effects of SGLT2 inhibitors on peak sodium channels within the physiological membrane voltage. A) Steady state voltage dependent INa inactivation curves of peak sodium current relative to maximal current in four different HEKNav1.5. cells: incubated with SGLT2 inhibitors (10μM, 1μM, 0.1μM) or incubated with 0.01% DMSO (control) for 4 hours, using the protocol showed on the right side. The grey box represented the physiological membrane voltage range (-90 mV to -65 mV). B) Steady state voltage dependent INa inactivation curves of peak sodium current density in HEKNav1.5 cells with or without SGLT2 inhibitors, with the grey box indicating the physiological membrane voltage range (-90 mV to -65 mV)Abstract BS52 Table 1Effects of Dapagliflozin on peak sodium current in four different HEKNav1.5 cells: incubated with SGLT2 inhibitors (10uM, 1uM, 0.1uM) or incubated with 0.01% DMSO (control) for 4 hours. Dapa= Dapagliflozin, DMSO= Dimethylsulfoxide, V50 act= mean midpoint of activation curves, Vrev=Reversal potential, P50 rec= P1-P2 time interval that causes 50% recovery of peak sodium current. Each value shows the mean±SEM of n=10 experiments in each group. * p<0.05, ** p < 0.01, *** p<0.0001 vs. control 10uM Dapa 1uM Dapa 0.1uM Dapa DMSO V50 act (mV) -30.41±1.911 -33.50±1.437* -32.46±1.159* -26.54±1.207 Vrev (mV) 55.81±3.065 57.05±5.385 57.87±1.845 54.90±2.649 P50 rec (ms) 15.86±1.822** 19.94±2.229** 17.49±0.5809*** 7.403±0.7205 Conflict of InterestNo

1 Harmala alkaloids are endogenous substances, which are involved in neurodegenerative disorders such as M. Parkinson, but some of them also have neuroprotective effects in the nervous system. 2 While several sites of action at the cellular level (e.g. benzodiazepine receptors, 5‐HT and GABAA receptors) have been identified, there is no report on how harmala alkaloids interact with voltage‐gated membrane channels. 3 The aim of this study was to investigate the effects of harmaline and harmane on voltage‐activated calcium‐ (ICa(V)), sodium‐ (INa(V)) and potassium (IK(V))‐channel currents, using the whole‐cell patch‐clamp method with cultured dorsal root ganglion neurones of 3‐week‐old rats. Currents were elicited by voltage steps from the holding potential to different command potentials. 4 Harmaline and harmane reduced ICa(V), INa(V) and IK(V) concentration‐dependent (10–500 μM) over the voltage range tested. ICa(V) was reduced with an IC50 of 100.6 μM for harmaline and by a significantly lower concentration of 75.8 μM (P<0.001, t‐test) for harmane. The Hill coefficient was close to 1. Threshold concentration was around 10 μM for both substances. 5 The steady state of inhibition of ICa(V) by harmaline or harmane was reached within several minutes. The action was not use dependent and at least partly reversible. 6 It was mainly due to a reduction in the sustained calcium channel current (ICa(L+N)), while the transient voltage‐gated calcium channel current (ICa(T)) was only partially affected. 7 We conclude that harmaline and harmane are modulators of ICa(V) in vitro. This might be related to their neuroprotective effects. British Journal of Pharmacology (2005) 144, 52–58. doi:10.1038/sj.bjp.0706024

In recent years, SGLT2 inhibitors have become an integral part of heart failure therapy, and several mechanisms contributing to cardiorenal protection have been identified. In this study, we place special emphasis on the atria and investigate acute electrophysiological effects of dapagliflozin to assess the antiarrhythmic potential of SGLT2 inhibitors. Direct electrophysiological effects of dapagliflozin were investigated in patch clamp experiments on isolated atrial cardiomyocytes. Acute treatment with elevated-dose dapagliflozin caused a significant reduction of the action potential inducibility, the amplitude and maximum upstroke velocity. The inhibitory effects were reproduced in human induced pluripotent stem cell-derived cardiomyocytes, and were more pronounced in atrial compared to ventricular cells. Hypothesizing that dapagliflozin directly affects the depolarization phase of atrial action potentials, we examined fast inward sodium currents in human atrial cardiomyocytes and found a significant decrease of peak sodium current densities by dapagliflozin, accompanied by a moderate inhibition of the transient outward potassium current. Translating these findings into a porcine large animal model, acute elevated-dose dapagliflozin treatment caused an atrial-dominant reduction of myocardial conduction velocity in vivo. This could be utilized for both, acute cardioversion of paroxysmal atrial fibrillation episodes and rhythm control of persistent atrial fibrillation. In this study, we show that dapagliflozin alters the excitability of atrial cardiomyocytes by direct inhibition of peak sodium currents. In vivo, dapagliflozin exerts antiarrhythmic effects, revealing a potential new additional role of SGLT2 inhibitors in the treatment of atrial arrhythmias.

Peripheral neurons with renal afferents exhibit a predominantly tonic firing pattern of higher frequency that is reduced to low frequencies (phasic firing pattern) in renal inflammation. We wanted to test the hypothesis that the reduction in firing activity during inflammation is due to high-activity tonic neurons switching from higher to low frequencies depending on altered sodium currents. We identified and cultivated afferent sensory neurons with renal projections from the dorsal root ganglia (Th11-L2). Cultivated neurons were incubated with the chemokine CXCL1 (1,5 nmol/ml) for 12 h. We characterized neurons as “tonic,” i.e., sustained action potential (AP) firing, or “phasic,” i.e., < 5 APs upon stimulation in the current clamp. Their membrane currents were investigated in a voltage clamp. Data analyzed: renal vs. non-renal and tonic vs. phasic neurons. Renal afferent neurons exposed to CXCL1 showed a decrease in tonic firing pattern (CXCL1: 35,6% vs. control: 57%, P < 0.05). Na+ and K+ currents were not different between control renal and non-renal DRG neurons. Phasic neurons exhibited higher Na+ and K+ currents than tonic resulting in shorter APs (3.7 ± 0.3 vs. 6.1 ± 0.6 ms, P < 0.01). In neurons incubated with CXCL1, Na+ and K+ peak current density increased in phasic (Na+: − 969 ± 47 vs. − 758 ± 47 nA/pF, P < 0.01; K+: 707 ± 22 vs. 558 ± 31 nA/pF, P < 0.01), but were unchanged in tonic neurons. Phasic neurons exposed to CXCL1 showed a broader range of Na+ currents ([− 365– − 1429 nA] vs. [− 412– − 4273 nA]; P < 0.05) similar to tonic neurons. After CXCL1 exposure, significant changes in phasic neurons were observed in sodium activation/inactivation as well as a wider distribution of Na+ currents characteristic of tonic neurons. These findings indicate a subgroup of tonic neurons besides mere tonic or phasic neurons exists able to exhibit a phasic activity pattern under pathological conditions.