Late Na(+) current and protracted electrical recovery are critical determinants of the aging myopathy.
Ontology highlight
ABSTRACT:
SUBMITTER: Signore S
PROVIDER: S-EPMC4638135 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:We investigated the transport characteristics of a square shape superconducting Ta thin film under DC electrical current bias along the diagonal direction. The resistance parallel (R∥) and perpendicular (R⊥) to the DC current, IDC, is measured with various magnetic fields. R∥ and R⊥ show contrasting dependence on IDC. First, the critical current of R∥ is smaller than that of R⊥. Second, R⊥ shows an unexpected reduction at current bias where R∥ shows a rapid increase near the transition from a flux flow state to a normal state. The intriguing anisotropic transport characteristics can be understood by the inhomogeneous current density profile over the square sample. Diagonal DC current induces an anisotropic current density profile where the current density is high near the biasing electrode and low at the center of the sample. Accordingly, the electrical transport in the perpendicular direction could remain less affected even near the critical current of R∥, which leads to the higher critical current in R⊥. Complicated conduction profile may also allow the anomalous reduction in the R⊥ before finally shifting to the normal state.
| S-EPMC7546633 | biostudies-literature
Project description:The late Na current is of pathophysiological importance for the heart. Ranolazine is an innovative anti-ischemic and antianginal agent that inhibits the late Na current, thereby reducing the Na-dependent Ca-overload, which improves diastolic tone and oxygen handling during myocardial ischemia. In addition, ranolazine seems to exert beneficial effects on diastolic cardiac function. Moreover, there are experimental and clinical data about its antiarrhythmic properties. A beneficial atrial selectivity of ranolazine has been suggested that may be helpful for the treatment of atrial fibrillation. The purpose of this review article is to discuss possible future clinical indications based on novel experimental and preclinical results and the significance of the available data.
| S-EPMC3406311 | biostudies-literature
Project description:Experimental data accumulated over the past decade show the emerging importance of the late sodium current (I(NaL)) for the function of both normal and, especially, failing myocardium, in which I(NaL) is reportedly increased. While recent molecular studies identified the cardiac Na(+) channel (NaCh) alpha subunit isoform (Na(v)1.5) as a major contributor to I (NaL), the molecular mechanisms underlying alterations of I(NaL) in heart failure (HF) are still unknown. Here we tested the hypothesis that I(NaL) is modulated by the NaCh auxiliary beta subunits. tsA201 cells were transfected simultaneously with human Na(v)1.5 (former hH1a) and cardiac beta(1) or beta(2) subunits, and whole-cell patch-clamp experiments were performed. We found that I(NaL) decay kinetics were significantly slower in cells expressing alpha + beta(1) (time constant tau = 0.73 +/- 0.16 s, n = 14, mean +/- SEM, P < 0.05) but remained unchanged in cells expressing alpha + beta(2) (tau = 0.52 +/- 0.09 s, n = 5), compared with cells expressing Na(v)1.5 alone (tau = 0.54 +/- 0.09 s, n = 20). Also, beta(1), but not beta(2), dramatically increased I(NaL) relative to the maximum peak current, I(NaT) (2.3 +/- 0.48%, n = 14 vs. 0.48 +/- 0.07%, n = 6, P < 0.05, respectively) and produced a rightward shift of the steady-state availability curve. We conclude that the auxiliary beta(1) subunit modulates I(NaL), produced by the human cardiac Na(+) channel Na(v)1.5 by slowing its decay and increasing I(NaL) amplitude relative to I(NaT). Because expression of Na(v)1.5 reportedly decreases but beta(1) remains unchanged in chronic HF, the relatively higher expression of beta(1) may contribute to the known I(NaL) increase in HF via the modulation mechanism found in this study.
| S-EPMC2744134 | biostudies-literature
Project description:AimTo compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na(+) current, HERG and Kv1.5 channel currents.MethodsWild-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.ResultsSuperfusion of 18?-glycyrrhetinic acid (18?-GA, 1-100 ?mol/L) blocked both the peak current (I(Na,P)) and late current (I(Na,L)) generated by WT and ?KPQ Nav1.5 channels in a concentration-dependent manner, while 18?-glycyrrhetinic acid (18?-GA) at the same concentrations had no effects. 18?-GA preferentially blocked I(Na,L) (IC(50)=37.2 ± 14.4 ?mol/L) to I(Na,P) (IC(50)=100.4 ± 11.2 ?mol/L) generated by ?KPQ Nav1.5 channels. In human atrial myocytes, 18?-GA (30 ?mol/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 18?-GA (100 ?mol/L) had no effects on HERG and Kv1.5 channel currents.Conclusion18?-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels.
| S-EPMC4010371 | biostudies-literature
Project description:BACKGROUND:Rapid delayed rectifier K+ current (IKr) and late Na+ current (INaL) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. METHODS:Physiological self AP-clamp was used to measure INaL and IKr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between IKr and INaL affects repolarization stability in health and disease conditions. RESULTS:We found comparable amount of net charge carried by IKr and INaL during the physiological AP, suggesting that outward K+ current via IKr and inward Na+ current via INaL are in balance during physiological repolarization. Remarkably, IKr and INaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block IKr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na+ channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit INaL sufficiently restored APD to control in both cases. Importantly, INaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, INaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by INaL inhibition, increased by IKr inhibition, and restored by combined INaL and IKr inhibitions. CONCLUSIONS:Our data demonstrate that IKr and INaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.
| S-EPMC7331791 | biostudies-literature
Project description:BackgroundLate-onset Parkinson's disease (LOPD) is a common neurodegenerative disorder and lacks disease-modifying treatments, attracting major attentions as the aggravating trend of aging population. There were numerous evidences supported that accelerated aging was the primary risk factor for LOPD, thus pointed out that the mechanisms of PD should be revealed thoroughly based on aging acceleration. However, how PD was triggered by accelerated aging remained unclear and the systematic prediction model was needed to study the mechanisms of PD.ResultsIn this paper, an improved PD predictor was presented by comparing with the normal aging process, and both aging and PD markers were identified herein using machine learning methods. Based on the aging scores, the aging acceleration network was constructed thereby, where the enrichment analysis shed light on key characteristics of LOPD. As a result, dysregulated energy metabolisms, the cell apoptosis, neuroinflammation and the ion imbalances were identified as crucial factors linking accelerated aging and PD coordinately, along with dysfunctions in the immune system.ConclusionsIn short, mechanisms between aging and LOPD were integrated by our computational pipeline.
| S-EPMC7288517 | biostudies-literature
Project description:BackgroundIntensive care unit acquired weakness (ICUAW), embraces an array of disorders labeled "critical illness polyneuropathy" (CIP), "critical illness myopathy" (CIM) or "critical illness polyneuromyopathy" (CIPNM). Several studies have addressed the various characteristics of ICUAW, but the recovery is still unclear.ObjectiveThe present review investigated the recovery and the long-term functional outcome of subjects with ICUAW, whether the types of ICUAW have different outcomes and whether there is any supporting evidence.MethodsLiterature search was performed from MEDLINE/PubMed, CINAHL, EMBASE, PeDro, Web of Science and Scopus. Inclusion criteria were: i) sample size including five or more subjects; ii) subjects who suffered from ICUAW and/or CIP, CIM and CIP/CIM; iii) ICUAW ascertained by EMG. Follow-ups longer than one year were defined as long-term.ResultsTwenty-nine studies met the inclusion criteria. In total, 788 subjects with ICUAW were enrolled: 159 (20.1%) died and 588 (74.6%) were followed. Of all the included patients, 613 (77.7%) had CIP, 82 (10.4%) CIM and 56 (7.1%) CIP/CIM. Overall, 70.3% of the subjects with ICUAW fully recovered. Seven (24.1%) studies had a follow-up longer than 1 year (range 2-8) with 173 (21.9%) subjects enrolled globally and 108 followed. Of these subjects, 88.8% gained full recovery. Most of the studies did not use proper functional scales and only 4 and 3 studies employed the Barthel scale and the Functional Independence Measure (FIM) scale. Differentiation between the types of ICUAW was performed in 7 studies, but only 3 studies reported that subjects with CIM had a better prognosis and earlier recovery than subjects with CIP/CIM.ConclusionsSubjects with ICUAW could achieve good recovery and could improve at follow-up. However, the quality of the published studies due to short follow-ups and the paucity of defined outcome measures require confirms.
| S-EPMC8831873 | biostudies-literature
Project description:This commentary on the review by DA Saint in the current issue of the British Journal of Pharmacology focuses on the pathological role of late I(Na) in the heart, the evidence supporting inhibition of late I(Na) as a therapeutic target in ischaemic heart disease, and the therapeutic applications and challenges for development of new late I(Na) inhibitors. Recent reports from a large clinical outcome trial (MERLIN) of ranolazine, a drug known to inhibit late I(Na), indicated that it was safe and reduced recurrent ischaemia and arrhythmic activity. In combination with other results indicating that inhibition of late I(Na) reduces ischaemia, myocardial Ca(2+) overload, and electrical and mechanical dysfunction when late I(Na) is increased, the new clinical trial results suggest that reduction of cardiac late I(Na) is safe and therapeutically beneficial.
| S-EPMC2275447 | biostudies-other
Project description:OBJECTIVE:The aim of the study was to estimate the prevalence of late-life community disability for adults 65 yrs and older with cardiovascular disease versus those without. This study also investigated the contributions of environmental and individual risk factors on late-life community disability for persons with cardiovascular disease. DESIGN:This is a secondary data analysis of the 2016 round of the National Health and Aging Trends Study. The study sample included community-dwelling Americans with cardiovascular disease (n = 1490) and without (n = 4819). Logistic regression was used to estimate associations between individual risk factors, environmental factors, and community disability for those with cardiovascular disease. RESULTS:Individuals with cardiovascular disease had a significantly higher prevalence of late-life community disability than those without (44.8% vs. 29.0%). For persons with cardiovascular disease, lack of transportation, home modification, and needing assistance with mobility increased the odds of community disability. Younger age and lower comorbidity were associated with decreased odds of community disability. When accounting for environmental factors in multivariate analyses, sex, race, and education were not significantly associated with community disability. CONCLUSION:Late-life community disability is highly prevalent for persons aging with cardiovascular disease. Intervention strategies to deter late-life community disablement should focus on improving access to transportation and improving the community environment in which older adults live.
| S-EPMC6705120 | biostudies-literature
Project description:The common polymorphism SCN5A-S1103Y (∼13% allelic frequency in African Americans) is a risk factor for arrhythmia, sudden unexplained death (SUD), and sudden infant death syndrome. Prompted by a case of autopsy-negative SUD in a 23-year-old African American man who collapsed while playing football, we hypothesized that S1103Y interacted with other SCN5A variants to pathologically modify sodium current (I(Na)). Mutational analysis of arrhythmia-associated genes in the victim revealed the variants SCN5A-R680H and SCN5A-S1103Y. These variants were made both separately and in the same cDNA construct of the alternative splice variant backgrounds (SCN5A-Q1077del and Q1077) and expressed in HEK293 cells. In the most abundant SCN5A-Q1077del, late I(Na) for S1103Y alone was not significantly different from wild type (WT). However, late I(Na) for R680H, R680H+S1103Y (coexpressed), and R680H/S1103Y (on the same cDNA) was increased 2.1-, 3.4-, and 3.6-fold, respectively, compared with WT. Intracellular acidosis (pH 6.7) increased late I(Na) for S1103Y, R680H, R680H+S1103Y, and R680H/S1103Y by 2.2-, 2.4-, 5.0-, and 5.5-fold, respectively, compared with WT at pH 6.7. Expression in the less abundant SCN5A-Q1077 showed no increased late I(Na). This is the initial report of a functional interaction for the common polymorphism S1103Y with another mutation in the major transcript Q1077del of SCN5A. The "double hit" and environmental factor of acidosis may have converged to cause arrhythmic sudden death in this case.
| S-EPMC3110896 | biostudies-literature