Late sodium current

BACKGROUND: Amiodarone (AMIO) is an antiarrhythmic drug with the pKa in the physiological range. Here, we explored how mild extracellular pH (pHe) changes shape the interaction of AMIO with atrial tissue and impact its pharmacological properties in the classical model of sea anemone sodium channel neurotoxin type 2 (ATX) induced late sodium current (INa-Late ) and arrhythmias. METHOD: Isolated atrial cardiomyocytes from male Wistar rats and human embryonic kidney cells expressing SCN5A Na+ channels were used for patch-clamp experiments...

Understanding medium spiny neuron (MSN) physiology is essential to understand motor impairments in Parkinson's disease (PD) given the architecture of the basal ganglia. Here, we developed a custom three-chambered microfluidic platform and established a cortico-striato-nigral microcircuit partially recapitulating the striatal presynaptic landscape in vitro using induced pluripotent stem cell (iPSC)-derived neurons. We found that, cortical glutamatergic projections facilitated MSN synaptic activity, and dopaminergic transmission enhanced maturation of MSNs in vitro...

OBJECTIVE: Long QT syndrome type 7 (Andersen-Tawil syndrome, ATS), which is caused by KCNJ2 gene mutation, often leads to ventricular arrhythmia, periodic paralysis and skeletal malformations. The development, differentiation and electrophysiological maturation of cardiomyocytes (CMs) changes promote the pathophysiology of Long QT syndrome type 7(LQT7). We aimed to specifically reproduce the ATS disease phenotype and study the pathogenic mechanism. METHODS AND RESULTS: We established a cardiac cell model derived from human induced pluripotent stem cells (hiPSCs) to the phenotypes and electrophysiological function, and the establishment of a human myocardial cell model that specifically reproduces the symptoms of ATS provides a reliable platform for exploring the mechanism of this disease or potential drugs...

BACKGROUND: The Scn3b gene encodes for Navβ3, a pivotal regulatory subunit of the fast sodium channel in cardiomyocytes. However, its mutation status in the Chinese population suffering from Brugada Syndrome (BrS) has not been characterized, and the contributory pathophysiological mechanisms to disease pathology remain undefined. METHODS AND RESULTS: A Scn3b (c.260C>T, p.P87l) mutation was identified in a patient with BrS of Chinese descent. Functional analyses demonstrated that sodium channel activation for the wild type, mutant samples, and co-expression of both commenced at -55 mv and peaked at -25 mv...

Pictured, described, speculated upon, for close to 400 years, the function of the rectal gland of elasmobranchs remained unknown. In the late 1950s Burger discovered that the rectal gland of Squalus acanthias secreted an almost pure solution of sodium chloride, isosmotic with blood, that could be stimulated by volume expansion of the fish. Twenty five years later, Stoff discovered that the secretion of the gland was mediated by adenyl cyclase. Studies since then have shown that Vasoactive intestinal peptide (VIP) is the neurotransmitter responsible for activating adenyl cyclase; however, the amount of circulating VIP does not change in response to volume expansion...

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, NaV 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that NaV s abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death...

Genetic variants of gene SCN5A encoding the alpha-subunit of cardiac voltage-gated sodium channel Nav 1.5 are associated with various diseases, including long QT syndrome (LQT3), Brugada syndrome (BrS1), and progressive cardiac conduction disease (PCCD). In the last decades, the great progress in understanding molecular and biophysical mechanisms of these diseases has been achieved. The LQT3 syndrome is associated with gain-of-function of sodium channels Nav 1.5 due to impaired inactivation, enhanced activation, accelerated recovery from inactivation or the late current appearance...

BACKGROUND/OBJECTIVES: This study aimed to assess the current mean daily intake of 10 food groups, analyze the sociodemographic factors associated with food consumption, and determine the associations between food consumption/dietary intake and the prevalence rates of obesity, type 2 diabetes (T2D), and hypertension (HTN) in Jakarta, Indonesia. SUBJECTS/METHODS: A total of 600 participants aged 20-85 yrs were included in this cross-sectional study. Food consumption and dietary habits were assessed using a food frequency questionnaire...

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO)...

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 (NaV ) channels in pituitary GH3 cells...

We aim to summarize selected late-breaking science on hypertension management strategies and disease presented at the 2023 American Heart Association (AHA) conference. The trials discussed below encompass stricter goals of blood pressure management and were expanded into different population groups from different countries with varied socioeconomic backgrounds and settings, collectively advancing our understanding of hypertension treatment and its impact on public health. We summarized the China Rural Health Care Project (CRHCP), a four-year study involving over 34,000 participants in rural China, emphasizing the potential of stricter blood pressure goals in lowering the incidence of all-cause dementia and cognitive impairment...

BACKGROUND: Major depression has a complex and multifactorial etiology constituted by the interaction between genetic and environmental factors in its development. OBJECTIVE: The aim of this study was to evaluate the effects of sodium butyrate (SD) on epigenetic enzyme alterations in rats subjected to animal models of depression induced by maternal deprivation (MD) or chronic mild stress (CMS). METHODS: To induce MD, male Wistar rats were deprived of maternal care during the first 10 days of life...

AIMS: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, often caused by pathogenic sarcomere mutations. Early characteristics of HCM are diastolic dysfunction and hypercontractility. Treatment to prevent mutation-induced cardiac dysfunction is lacking. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a group of antidiabetic drugs that recently showed beneficial cardiovascular outcomes in patients with acquired forms of heart failure. We here studied if SGLT2i represent a potential therapy to correct cardiomyocyte dysfunction induced by an HCM sarcomere mutation...

A specific genetic variant associated with atrial fibrillation risk, rs17171731, was identified as a regulatory variant responsible for controlling FAM13B expression. The atrial fibrillation risk allele decreases FAM13B expression, whose knockdown alters the expression of many genes in stem cell-derived cardiomyocytes, including SCN2B , and led to pro-arrhythmogenic changes in the late sodium current and Ca2+ cycling. Fam13b knockout mice had increased P-wave and QT interval duration and were more susceptible to pacing-induced arrhythmias vs control mice...

The vast majority of antianginal drugs decrease heart rate and or blood pressure levels or the inotropic status of the left ventricle to decrease MVO2 and thus anginal symptoms. Ranolazine presents a completely different mechanism of action, which reduces the sodium-dependent calcium overload inhibiting the late sodium current. Current ESC guidelines for the management of angina in patients with chronic coronary symptoms recommend the use of several drugs such as ranolazine, b-blockers, calcium channel blockers, long-acting nitrates, ivabradine, nicorandil and trimetazidine for angina relief...

BACKGROUND: Bupleurum (Bup), is a traditional effective medicine to treat colds and fevers in clinics. Multiple studies have demonstrated that Bup exhibites various biological activities, including cardioprotective effects, anti-inflammatory, anticancer, antipyretic, antimicrobial, and antiviral effects, etc. Currently, the effects of Bup on cardiac electrophysiology have not been reported yet. METHODS: Electrocardiogram recordings were used to investigate the effects of Bup on aconitine-induced arrhythmias...

Cardiac ion currents may compensate for each other when one is compromised by a congenital or drug-induced defect. Such redundancy contributes to a robust repolarization reserve that can prevent the development of lethal arrhythmias. Most efforts made to describe this phenomenon have quantified contributions by individual ion currents. However, it is important to understand the interplay between all major ion channel conductances, as repolarization reserve is dependent on the balance between all ion currents in a cardiomyocyte...

A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca2+ ) homeostasis. We investigated the effects of a KD on Ca2+ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD...

BACKGROUND: Recent evidence revealed that glucose fluctuation might be more likely to cause arrhythmia than persistent hyperglycemia, whereas its mechanisms were elusive. We aimed to investigate the effect of glucose fluctuation on the occurrence of ventricular arrhythmia and its mechanism. METHODS: Streptozotocin (STZ) induced diabetic rats were randomized to five groups: the controlled blood glucose (C-STZ) group, uncontrolled blood glucose (U-STZ) group, fluctuated blood glucose (GF-STZ) group, and GF-STZ rats with 100 mg/kg Tempol (GF-STZ + Tempol) group or with 5 mg/kg KN93 (GF-STZ + KN93) group...

BACKGROUND: Over a hundred genetic loci have been associated with atrial fibrillation (AF). But the exact mechanism remains unclear and the treatment needs to be improved. OBJECTIVE: This study aims to investigate the mechanism and potential treatment of NPPA mutation associated AF. METHODS: The Nppa KI (p.I137T) rats were generated and cardiac function was evaluated. Blood pressure was recorded by a tail cuff system. The expression levels were measured by RT-PCR, ELISA or western blot, and RNA sequence analysis...