Electrical remodeling of membrane ionic channels of hypertrophied ventricular myocytes from spontaneously hypertensive rats

To study the difference in membrane ionic currents between hypertrophied and normal myocytes and to explore the electrical remodeling of hypertrophied myocytes Methods Membrane ionic channels were studied in enzymatically dispersed spontaneously hypertensive rats (SHRs) left ventricular myocytes using the whole cell configuration of patch clamp technique, with normal Wistar rats ventricular myocytes as controls We observed depolarizing currents (sodium current, I Na ; L type calcium current, L I Ca ) and repolarizing currents (inward rectifier potassium current, I K1 ; delayed rectifier potassium current, I K; transient outward potassium current, I to ) and compared the differences between normal and hypertrophied myocytes Results The heart to body weight ratio of Wistar rats and SHRs was 3 70±0 29?mg/g and 5 66±0 46?mg/g, respectively ( P <0 001), and the mean cell membrane capacitances were 189 94±56 59?pF and 280 68±67 98?pF, respectively ( P <0 05) These differences suggest that SHRs have heart hypertrophy and hypertrophied myocytes The amplitude of L I ca of SHRs (1944±466 8?pA) was significantly greater than that of Wistar rats (1136±383 3?pA) ( P <0 001), and the current density was 6 93±1 71?pA/pF and 6 19±2 85?pA/pF respectively when normalized to cell capacitance, and the slow inactivation time constant of SHRs was significantly prolonged (56 01±13 36?ms vs 43 63±17 89?ms, P <0 001) The amplitude of I Na of SHRs (6132 5±1162 9?pA) was significantly greater than that of Wistar rats (3613 9±794 44?pA) ( P <0 001), but there was no difference when normalized to cell capacitance (24 61±6 72?pA/pF vs 24 95±6 99?pA/pF) Channel activation and inactivation time constants were also the same The amplitude of I K of SHRs (3461 5±1967 10?pA) was greater than that of Wistar rats (2302 4±893 72?pA) ( P <0 05), but there was no difference when normalized to cell capacitance (12 38±5 46 ?pA/pF vs 11 86±3 59?pA/pF) The inward portion of I K1 of SHRs was significantly lower than that of Wistar rats (11 3±2 26?pA/pF vs 14 3±3 00?pA/pF, P <0 05), but there was no difference in the outward portion (2 360±0 86?pA/pF vs 2 957±1 27? pA/pF) The current density of I to of SHRs (8 21±6 64?pA/pF) was significantly lower than that of Wistar rats (19 16±6 17?pA/pF) ( P <0 001), but channel kinetics were similar, suggesting that the reduction of I to may result from the decrease in channel number Conclusions Membrane ionic current changes of hypertrophied left ventricular myocytes in SHRs include: 1 there was an increase of L I ca , I Na and I k, but the current density was similar to that in normal myocytes, indicating that channel numbers increase as the myocytes become hypertrophied; 2 I to was small in hypertrophied ventricular myocytes and its current density was even smaller, indicating that channel numbers decrease as the myocytes enlarge The former is recognized as a physiologically compensatory change which does not lead to electrophysiological disturbance; the latter is viewed as pathological change, where the reduction of I to may lead to a repolarizing delay in myocytes, prolongation of the action potential and the occurrence of arrhythmias because of repolarizing heterogeneity Therefore, the reduction of I to in hypertrophied myocytes should be recognized as a significant or substantial change of electrical remodeling

Lithium-Ion Charged Polymer Channels Flattening Lithium Metal Anode

The concentration difference in the near-surface region of lithium metal is the main cause of lithium dendrite growth.Resolving this issue will be key to achieving high-performance lithium metal batteries(LMBs).Herein,we construct a lithium nitrate(LiNO_(3))-implanted electroactiveβphase polyvinylidene fluoride-co-hexafluoropropylene(PVDF-HFP)crystalline polymorph layer(PHL).The electronegatively charged polymer chains attain lithium ions on the surface to form lithium-ion charged channels.These channels act as reservoirs to sustainably release Li ions to recompense the ionic flux of electrolytes,decreasing the growth of lithium dendrites.The stretched molecular channels can also accelerate the transport of Li ions.The combined effects enable a high Coulombic efficiency of 97.0%for 250 cycles in lithium(Li)||copper(Cu)cell and a stable symmetric plating/stripping behavior over 2000 h at 3 mA cm^(-2)with ultrahigh Li utilization of 50%.Furthermore,the full cell coupled with PHL-Cu@Li anode and Li Fe PO_(4) cathode exhibits long-term cycle stability with high-capacity retention of 95.9%after 900 cycles.Impressively,the full cell paired with LiNi_(0.87)Co_(0.1)Mn_(0.03)O_(2)maintains a discharge capacity of 170.0 mAh g^(-1)with a capacity retention of 84.3%after 100 cycles even under harsh condition of ultralow N/P ratio of 0.83.This facile strategy will widen the potential application of LiNO_(3)in ester-based electrolyte for practical high-voltage LMBs.

Expression levels of ionic channels in atrial myocytes are changeable by ambient high hydrostatic pressure stimulation

Background Atrial fibrillation （AF） is the most common arrhythmia encountered in clinical practice and hy- pertension has been well established to be the most common medical condition associated with AF. The present study aimed to explore the expression of ionic channels in atrial myocytes, the main mechanisms of atrial electrical remodeling, under ambient pressure stimulation. Methods A resealable device that could provide and maintain a certain pressure was designed and used. Subconfluent cells were maintained in a pressure culture device which placed in a carbon dioxide incubator for 24 h. The pressure gradient was set to 0 mmHg, 20 mmHg and 40 mmHg. The mRNA and protein levels of the calcium channel, potassium channel and sodium channel were assayed using real-time PCR, and Western blot respectively. Results We found that mRNA and protein expression of Cav1.2 and protein expression of Cav3.1, Kv11.1 and Kv4.3 are significantly decreased after pressure stimulation. Pressure stimulation up-regulated the mRNA and protein expression of Kv1.5 and Kir2.1 but could not regulate mRNA or protein expression of Nay1.5. Conclusions Our results represent a potential pathogenic mechanism of hypertension involved in atrial electrical remodeling and provide enlightening insights to the prevention and treatment of AF.

MODELING AND SIMULATION OF E1784K MUTATION AND SODIUM IONIC CHANNEL DISEASES

In the clinical reports, the E1784K mutation in SCN5A is recognized as a phenotypic overlap between the long QT syndrome （LQT3） and the Brugada syndrome （BrS） in the characteristics of electrocardiograms （ECGs） since the mutation can influence sodium channel functions. However it is still unclear if the E1784K mutation-induced sodium ionic channel alterations account for the overlap at tissue level. Thsu, a detailed computational model is developed to underpin the functional impacts of the E1784K mutation on the action potential （AP）, the effective refractory period （ERP） and the abnormal ECG. Simulation results stlggest＇that the E1784K mutation-induced sodium channel alterations are insufficient to produce the phenotypic overlap between LQT3 and BrS, and the overlap may arise from the complicated effects of the E1784K mutation-induced changes in sodium channel currents with an increase of the transient outward current ITo or a decrease of the L-type calcium current ICaL .

Ionic Remodeling and Direct Effects of Valsartan on Ionic Currentsin Human Atrial Myocytes with Atrial Fibrillation

Objectives Previous studies demonstrated that angiotensin receptor antagonists had effects on some potassium channels in guinea pig myo- cytes and cloned channels that expressed in human car- diac myocytes. This study determined the direct effects of Valsartan on IcaL, INa, IKur, IKl and Itol in isolated human atrial myocytes. Methods and Results Specimens of right atrial appendage tissue were ob- tained from 39 patients with coronary artery and valvu- lar heart diseases during cardiopuhnonary bypass proce- dure. Pre - operation cardiac rhythm was sinus (SR) in 19 patients and was atrial fibrillation (AF) in the others. Single atrial myocyte was isolated by enzymatic dissociation with the chunk method. The ionic currents were recorded using the whole cell configuration of the voltage clamp technique. ICaL and Itol densities in AF patients were significantly lower than those in SR pa- tients by 74% and 60% , respectively, while IK1 density was significantly higher by 34% at command potential of - 120 mV. With 10 μmol/L Valsartan, INa density was significantly decreased by 59% in SR patients and by 66% in AF patients. IKur and IK1 density were sig- nificantly decreased in only AF patients by 31% and 23% , respectively. Conclusions Conclusions De- creased ICaL and Itol and increased IK1 at hyperpolarizing potentials in AF patients' atrial myocytes may result from the electrophysiological remodeling by AF. Val- sartan significantly decreases INa, IK1 and IKur current densities in AF patients' myocyte, but decreases only INa in SR patients' myocyte, suggesting that Valsartanmay be beneficial to the recovering of remolded atria.

Frameworked electrolytes:Ionic transport behavior and high mobility for solid state batteries

All solid-state batteries(ASSBs)are the holy grails of rechargeable batteries,where extensive searches are ongoing in the pursuit of ideal solid-state electrolytes.Nevertheless,there is still a long way off to the satisfactorily high(enough)ionic conductivity,long-term stability and especially being able to form compatible interfaces with the solid electrodes.Herein,we have explored ionic transport behavior and high mobility in the sub-nano pore networks in the framework structures.Macroscopically,the frameworked electrolyte behaves as a solid,and however in the(sub)-nano scales,the very limited number of solvent molecules in confinement makes them completely different from that in liquid electrolyte.Differentiated from a liquid-electrolyte counterpart,the interactions between the mobile ions and surrounding molecules are subject to dramatic changes,leading to a high ionic conductivity at room temperature with a low activation energy.Li+ions in the sub-nano cages of the network structure are highly mobile and diffuse rather independently,where the rate-limiting step of ions crossing cages is driven by the local concentration gradient and the electrostatic interactions between Li^(+)ions.This new class of frameworked electrolytes(FEs)with both high ionic conductivity and desirable interface with solid electrodes are demonstrated to work with Li-ion batteries,where the ASSB with LiFePO_(4)shows a highly stable electrochemical performance of over 450 cycles at 2℃ at room temperature,with an almost negligible capacity fade of 0.03‰ each cycle.In addition,the FE shows outstanding flexibility and anti-flammability,which are among the key requirements of large-scale applications.

Research Advance on the Mechanism of Cadmium Transport in Rice

Soils in part of rice production areas have been seriously contaminated by cadmium （Cd）. Rice with high Cd content over allowable limit produced in these areas is widely concerned. Low accumulation varieties can remarkably decrease the Cd content in rice as well as the risk of food safety. The translocation of Cd either from soil to root system or from roots to aboveground parts is identified by a lot of ion transport proteins. Transport efficiency of Cd in some rice varieties is regulated by special metal ionic transporters. However, most varieties transport Cd by cation transporters or universal ionic transporters. Both the expression levels and time of gens controlling ionic transporters directly influence the Cd transport rates inside rice plant and the accumulation amount in different organs. Screening and utilizing specific Cd transport genes are the genetic basis of breeding low accumulation varieties.

The Quantum-Mechanical Sensitive Na/K Pump Is a Key Mechanism for the Metabolic Control of Neuronal Membrane Function

At present, there are relevant scientific materials on the cellular and molecular mechanisms of electrogenic Na/K pump function and structure, as well as on the potential- and ligand-activated ionic channels in the membrane. However, the role of electrogenic Na/K pump in regulation of semipermeable properties of cell membrane has not been elucidated yet, which is due to the fact that our knowledge about the biophysical properties of cell membrane is based on the conductive membrane theory of Hodgkin-Huxley-Katz, which is developed on internally perfused squid axon and lacks intracellular metabolism. Thus, the accumulated abundance of data on the role of G-proteins-dependent intracellular signaling system in regulation of Na/K pump activity and biophysical properties of cell membrane presumes fundamental revision of some statements of membrane theory. The aim of the present review is to briefly demonstrate our and literature data on cell hydration-induced auto-regulation of Na/K pump as well as on its role in metabolic control of semipermeable properties and excitability of neuronal membrane, which are omitted in the study of internally perfused squid axon.

Acid-sensing ion channels: potential therapeutic targets for neurologic diseases

Maintaining the physiological pH of interstitial fluid is crucial for normal cellular functions.In disease states,tissue acidosis is a common pathologic change causing abnormal activation of acid-sensing ion channels(ASICs),which according to cumulative evidence,significantly contributes to inflammation,mitochondrial dysfunction,and other pathologic mechanisms(i.e.,pain,stroke,and psychiatric conditions).Thus,it has become increasingly clear that ASICs are critical in the progression of neurologic diseases.This review is focused on the importance of ASICs as potential therapeutic targets in combating neurologic diseases.

Identification of common genetic variants in KCNQ family genes associated with gastric cancer survival in a Chinese population

The KCNQ family of genes(KCNQ1–KCNQ5),encoding voltage-gated K+(Kv)channels,have been demonstrated to play potential pathophysiological roles in cancers.However,the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear.In this study,a large-scale cohort comprising 1135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival(OS).Based on the survival evaluation of all five KCNQ family genes,KCNQ1 was selected for subsequent genetic analysis.In both Cox regression model and stepwise Cox regression model used to evaluate survival-related genetic variants,we found that KCNQ1 rs10832417G>T was associated with an increased OS in gastric cancer patients(adjusted hazards ratio[HR]=0.84,95%confidence interval[CI]:0.72–0.98,P=0.023).Subsequently,a nomogram was constructed to enhance the prognostic capacity and clinical translation of rs10832417 variants.The rs10832417 T allele was predicted to increase the minimum free energy of the secondary structure.Furthermore,we observed that gastric cancer patients with downregulated KCNQ1expression had a poorer survival across multiple public datasets.The findings of the present study indicate that KCNQ1 rs10832417 may serve as an independent prognostic predictor of gastric cancer,providing novel insights into the progression and survival of the disease.

Effects of Simvastatin on Ion Channel Currents in Ventricular Myocytes from Acute Infarcted Heart of Normocholesterolemic Rabbits

Objectives To investigate the effects of simvastatin on membrane ionic currents in left ventricular myocytes of rabbit heart suffering from acute myocardial infarction （ AMI）, so as to explore the ionic mechanism of statin treatment for antiarrhythmia. Methods Forty-five New Zealand rabbits were randomly divided into three groups： AMI group, simvastatin intervention group （ Statin group） and sham-operated control group （CON）. Rabbits were infarcted by ligation of the left anterior descending coronary artery after administration of oral simvastatin 5 mg · kg^-1·d^-1 （Statin group） or placebo （AMI group） for 3 days. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region 72 h later. Whole cell patch clamp technique was used to record membrane ionic currents, including sodium current （INa）, L-type calcium current （Ica-L） and transient outward potassium current （Ito）. Results （1） There was not significant difference in serum cholesterol concentration among three groups. （2） The peak INa current density （at -30 mV） was significantly decreased in AMI group （ -25.26±5.28, n = 13 ）, comparing with CON （ - 42. 78± 5.48, n = 16）, P 〈 0. 05, while it was significantly increased in Statin group （ - 39.83 ±5.65 pA/pF, n = 12） comparing with AMI group, P 〈0. 01 ; The peak Ica-L current density （ at 0 mV） was significantly decreased in AMI group （ -3. 43 ±0. 92 pA/pF, n = 13） comparing with CON （ -4. 56 ±1.01 pA/pF, n = 15）, P 〈0. 05, while it was significantly increased in Statin group （ -4. 18±0. 96 pA/pF, n = 12） comparing with AMI group, P 〈0. 05; The Ito current density （ at ＋ 60 mV） was significantly decreased in AMI group （ 11.41 ± 1.94 pA/pF, n = 13 ） comparing with CON （17.41 ±3.13 pA/pF, n = 15）, P 〈0. 01, while it was significantly increased in Statin group （16. 11 ± 2. 43 pA/pF, n = 14） comparing with AMI group, P 〈 0. 01. Conclusions AMI induces significant down-regulation of INa, Ica-L and Ito. Pretreatment with simvastatin could attenuate this change without lowering the serum cholesterol level, suggesting that simvastatin could reverse this electrical remodeling, thus contributing to the ionic mechanism of statin treatment for antiarrhythmia.

Cardioprotective effects of simvastatin on reversing electrical remodeling induced by myocardial ischemia-reperfusion in normocholesterolemic rabbits

Background Recent studies have revealed that pretreatment with statin is effective in preventing arrhythmia, but its electrophysiological mechanism is unclear. This study was conducted to investigate the cardioprotective effects of simvastatin on reversing electrical remodeling in left ventricular myocytes of rabbit heart undergoing ischemia-reperfusion, so as to explore the ionic mechanism responsible for the anti-arrhythmic effect of statin. Methods Forty-five rabbits were randomly divided into three groups： ischemic-reperfusion group （I-R）, simvastatin intervention group （Statin） and sham-operated control group （CON）. Anesthetized rabbits were subjected to 30-minute ischemia by ligation of the left anterior descending coronary artery and a 60-minute reperfusion after a 3-day administration of oral simvastatin of 5 mg-kg^-1.d^-1 in the Statin group or a placebo in the I-R group. Single ventricular myocytes were isolated enzymatically from the epicardial zone of the infracted region dedved from the hearts in the I-R and Statin group and the same anatomical region in the CON animals. The whole cell patch-clamp technique was used to record membrane ionic currents, including sodium current （IRa）, L-type calcium current （Ica-L） and transient outward potassium current （Ito）. Simultaneously, the level of serum cholesterol was examined. Results There was no significant difference in the serum cholesterol concentration among the three groups. The peak IRa current density （at -30 mV） was significantly decreased in I-R （（22.46±5.32） pA/pF, n=12） compared with CON （（42.78±5.48） pA/pF, n=16, P〈0.01） and Statin （（40.66±5.89） pA/pF, n=15, P〈0.01）, while the peak IRa current density in the Statin group was not different from CON （P〉0.05）. The peak ICa-L current density （at 0 mV） was significantly increased in I-R （（4.34±0.92） pA/pF, n=15） compared with CON （（3.13±1.22） pA/pF, n=13, P〈0.05） and Statin （（3.46±0.85） pNpF, n=16, P〈0.05）, while the Peak ICa-L current density in Statin was not different from CON （P〉0.05）. The Ito current density （at ＋60mV） was significantly decreased in I-R （（9.49＋1.91） pA/pF, n=-11） compared with CON （（17.41±3.13） pA/pF, n=15, P〈0.01） and Statin （（14.54±2.41） pA/pF, n=11, P〈0.01）, although there was a slight reduction in the Statin group compared with CON （P〈0.05）. Conclusions It is implied that ischemia-reperfusion induces significant down-regulation of IRa and Ito and up-regulation of ICa-L, which may underlie the altered electrical activity and long abnormal transmembrane action potential duration of the surviving ventricular myocytes, thus contributing to ventricular arrhythmias during acute ischemia-reperfusion period. Pretreatment with simvastatin could attenuate these changes and reverse this electrical remodeling without lowering the serum cholesterol level, contributing to the ionic mechanism of statin in treatment of arrhythmia independent of a decrease in cholesterol.