Long-term treatment with ivabradine in transgenic atrial fibrillation mice counteracts hyperpolarization-activated cyclic nucleotide gated channel overexpression.

INTRODUCTION: Recent studies have demonstrated that ivabradine (IVA), is a selective inhibitor of funny current (If) and exerts antiarrhythmic effects in the settings of various diseases such as heart failure and myocardial ischemia. However, little is known regarding the effects of long-term IVA treatment on If current and hyperpolarization-activated cyclic nucleotide gated (HCN) channel overexpression. METHODS AND RESULTS: We investigated both the If current and HCN channel expression in wild-type (WT) mice and transgenic (TG) atrial fibrillation (AF) mice (heart-specific overexpressing of (pro) renin receptor TG mice) and examined the effects of IVA on the If current and HCN channel expression, and whether those effects were sufficient to prevent an AF episode. Compared with WT mice, the If current density (at -170 mV: TG, -39.6 ± 4.6 pA/pF; WT, -26.9 ± 3.0 pA/pF; P < 0.001) and activation kinetics (V1/2 : TG, -109.45 ± 1.35 mV; WT, -128.20 ± 1.65 mV), as well as HCN2 and HCN4 messenger RNA expression and HCN4 protein expression were significantly increased in the atrial myocytes of TG mice. After 4 months of IVA treatment (7 mg/kg per day orally) the effects of IVA on TG AF mice were accompanied by the inhibition of upregulation of HCN2 and HCN4 protein expression in atrial tissue, and then resulted in a uniform If loss of function. Furthermore, we observed that ivabradine significantly decreased the incidence of AF in the TG mice (41.2% in TG mice, 16.7% in TG + IVA mice; P < 0.01). CONCLUSION: IVA reduced the incidence of AF in mice, and the antiarrhythmic effects of IVA are not limited to heart rate reduction, as they partially counteract HCN overexpression and reverse electrophysiological cardiac remodeling by attenuating If gain-of-function.

Association between cardiac changes and stress, and the effect of peroxisome proliferator-activated receptor-γ on stress-induced myocardial injury in mice.

This study was aimed to investigate the effect of stress induced by high-intensity exercises on the cardiovascular system. In the epidemiological investigation, 200 subjects (test group) engaged in special high-intensity exercises, and 97 who lived and worked in the same environment and conditions as those in the test group, but did not participate in the exercises served as controls. In the second part of the study, 50 mice were randomly divided into control group, exhaustive swimming group, white noise group, exhaustive swimming plus white noise group, and pioglitazone intervention group. The results showed that the plasma concentrations of the myocardial injury markers heart fatty acid-binding protein (H-FABP), C-reactive protein (CRP), ß-endorphin (ß-EP) and levels of psychological stress were significantly increased in test group as compared with control group; special high-intensity exercises resulted in a significant elevation of the incidence of cardiac arrhythmias. Animal experiments showed that the plasma levels of corticosterone (CORT) and troponin I (TnI) were raised while the level of SOD was reduced in exhaustive swimming group, white noise group, and exhaustive swimming plus white noise group. The expression levels of PPARγ mRNA and protein were decreased in myocardial tissues in these groups as well. HE staining showed no remarkable change in myocardial tissues in all the groups. Treatment with pioglitazone significantly decreased the plasma levels of TnI and CORT, while increased the level of SOD and the expression levels of PPARγ mRNA and protein. It was concluded that the high-intensity exercises may induce a heavy physical and psychological stress and predispose the subjects to accumulated fatigue and sleep deprivation; high-intensity exercises also increases the incidence of arrhythmias and myocardial injury. PPARγ may be involved in the physical and psychological changes induced by high-intensity exercises.

Allocryptopine and benzyltetrahydropalmatine block hERG potassium channels expressed in HEK293 cells.

AIM: Allocryptopine (ALL) is an alkaloid extracted from Corydalis decumbens (Thunb) Pers. Papaveraceae, whereas benzyltetrahydropalmatine (BTHP) is a derivative of tetrahydropalmatine extracted from Corydalis ambigua (Pall) Cham et Schlecht. The aim of this study was to investigate the effects of ALL and BTHP on the human ether-a-go-go related gene (hERG) current expressed in HEK293 cells. METHODS: Cultured HEK293 cells were transiently transfected with hERG channel cDNA plasmid pcDNA3.1 using Lipofectamine. The whole-cell current IHERG was evoked and recorded using Axon MultiClamp 700B amplifier. The drugs were applied via supserfusion. RESULTS: Both ALL and BTHP reversibly suppressed the amplitude and density of IHERG in concentration- and voltage-dependent manners (the respective IC50 value was 49.65 and 22.38 µmol/L). BTHP (30 µmol/L) caused a significant negative shift of the steady-state inactivation curve of IHERG, while ALL (30 µmol/L) did not affect the steady-state inactivation of IHERG. Furthermore, BTHP, but not ALL, shortened the time constants of fast inactivation and slow time constants of deactivation of IHERG. But both the drugs markedly lengthened the time constants for recovery of IHERG from inactivation. Using action potential waveform pulses, it was found that both the drugs at 30 µmol/L significantly suppressed the current densities in the late phase of action potential, but did not significantly affect the current densities in the early phase of action potential. CONCLUSION: Both ALL and BTHP derived from Chinese herbs potently block hERG current.

[Age-related changes in transient outward potassium current of rat ventricular myocyte].

The study aimed to investigate the age-related changes and drug reactions of transient outward potassium current (Ito) of ventricular myocytes. Twenty-eight Sprague Dawley rats were divided into young (3-5 months), adult (13-15 months) and aged (22-24 months) groups, and Ito currents of isolated myocytes from each group were recorded respectively by patch-clamp. The perfusion of 2.0 mmol/L 4-AP or 1.0 µmol/L isoproterenol was added respectively in each group, and the changes of Ito were observed. In comparison with young and adult groups, Ito densities of ventricular myocytes in aged group was significantly increased, the curve of steady-state activation of Ito shifted to the left, the close-state inactivation rate significantly decreased, and recovery rate from the steady-state inactivation became quicker. However, no significant changes could be detected for the Ito steady-state inactivation of ventricular myocytes in aged group. The similar responsiveness to 4-AP was observed in all three groups, but the responsiveness to isoproterenol was weaker in the aged group (55.9%) than in the other two groups (127.5% and 125.8%). In conclusion, the results show that Ito of rat ventricular myocyte of aging heart has increased current density and decreased response to isoproterenol.

Relationship between serum uric acid and estimated glomerular filtration rate in adolescents aged 12-19 years with different body mass indices: a cross-sectional study.

Background: Globally, chronic kidney disease (CKD) is a growing public health concern. Serum uric acid (SUA) is an easily detectable and readily available biochemical indicator that has long been recognized as an independent risk factor for CKD. In addition, studies have indicated a potential relationship between SUA and body mass index (BMI). However, studies on the effect of SUA levels on the estimated glomerular filtration rate (eGFR) in adolescents with different BMIs are very rare. Methods: Weighted multiple regression analysis was used to estimate the independent relationship between SUA and log-transformed eGFR. Additionally, we used a weighted generalized additive model and smooth curve fitting to describe the nonlinear relationships in the subgroup analysis. Results: First, SUA was negatively associated with log-transformed eGFR even after adjusting for all covariates (ß=-0.0177, 95% CI: -0.0203-0.0151, P<0.0001). Second, the results of the stratified analysis found that after adjusting for all covariates, the decrease in log-transformed eGFR due to changes in per SUA levels (Per 1, mg/dL increase) was elevated in female adolescents (ß=-0.0177, 95% CI: -0.0216, -0.0138, P<0.0001), adolescents aged 12-15 years (ß=-0.0163, 95% CI: -0.0200, -0.0125, P<0.0001) and black (ß=-0.0199, 95% CI: -0.0251, -0.0148, P<0.0001) adolescents. Furthermore, we found that adolescents with a higher BMI had higher SUA levels, and the effect of SUA on eGFR was significantly higher in underweight adolescents (ß=-0.0386, 95% CI: (-0.0550, -0.0223), P<0.0001). Conclusion: SUA was negatively associated with the eGFR in adolescents aged 12-19 years. Furthermore, we found for the first time that SUA affects the eGFR differently in adolescents with different BMIs. This effect was particularly significant in underweight adolescents.

Derivation of new resistance principle on flow-induced morphological response of flexible vegetation.

Water flow under vegetated environments is a noteworthy research topic in environmental hydraulics and restoration ecology, and this research is particularly important for maintaining water transport and streambed stability in water ecosystems. The calculation of the resistance coefficient in vegetated water flow is the core of this research. But there are still problems such as complex expressions and low simulation accuracy in this research field. To solve this scientific problem, this research, based on the theoretical study of environmental hydraulics and genetic algorithm, selected three basic parameters of vegetation submergence, resistance length and curvature degree, and successfully constructed the formula for calculating the resistance coefficient for flexible vegetated flow by using a wide range of data sets. New quantitative relationship between the drag coefficient and the relative roughness of flexible vegetation was established in this study. The formula of drag coefficients for flexible vegetation conditions has a more concise form and can be successfully applied to both flexible and rigid vegetation. As flexible vegetation is deformed under the action of water flow, and the quantitative expressions of Vogel number and relative roughness are given quantitatively through the analysis of its physical properties. Overall, this study improves the basic theoretical study of vegetated flow in environmental fluid dynamics and provides scientific theoretical support for vegetation restoration.

Prevalence and correlates of elder neglect in the community-dwelling Chinese population: New evidence from the CLHLS study.

Background: This study aimed to explore the prevalence of elder neglect (EN) and its associated factors among community-based Chinese older adults. Methods: We used data from the 2018 phase of a nationwide cross-sectional study, the Chinese Longitudinal Healthy Longevity Survey (CLHLS), which recruited 15,854 older adults to complete the study interviews that incorporated six dimensions of EN, namely, life neglect, social isolation, medical neglect, poor living situation, family neglect, and social neglect. Multivariate logistic regression was used to explore factors associated with EN. Results: We included demographic factors, chronic diseases, cognitive function, and daily activity function in our comprehensive analysis and showed that they had different effects on the six EN dimensions. Different demographic factors such as gender, age, marriage, education, occupation, residence, and household income were included in the comprehensive analysis, and the results showed that these factors had different effects on the six dimensions of EN. Next, we found that older adults with chronic diseases are prone to life neglect, medical neglect, and residential environment neglect. Older adults with better cognitive abilities were less likely to be neglected, and a decline in daily activity capacity has been linked to EN in older adults. Conclusion: Future studies are needed to identify the health effects of these associated factors, develop prevention strategies for EN, and improve the quality of life of older adults living in communities.

[Effect of carvedilol on T-type calcium current in myocytes of non-infarcted area of the rabbit healed myocardial infarction].

This article reports the investigation of the effect of carvedilol (Car) on T-type calcium current (I(Ca,T)) of noninfarcted ventricular myocytes in rabbit models of healed myocardial infarction (HMI). Rabbits with left anterior descending artery ligation were prepared and allowed to recover for 8 weeks, as HMI group. Animals undergoing an identical surgical procedure without coronary ligation were served as the sham-operated group (sham group). Whole cell voltage-clamp techniques were used to measure and compare currents in cells from the different groups. Noting that I(Ca,T) density in HMI cells increased markedly to -2.36 +/- 0.12 pA/pF (at -30 mV) compared with cells of sham, where little I(Ca,T) (-0.35 +/- 0.02 pA/pF) was observed. Meanwhile, further analysis revealed a significant hyperpolarizing shift of steady-state activation curve of I(Ca,T) in HMI cells, where the time constants of deactivation were prolonged and the time of recovery from inactivation was shortened. Finally, the amplitude of I(Ca,T) was increased. Carvedilol (1 micromol x L(-1)) was found to decrease the amplitude of I(Ca,T) to -1.38 +/- 0.07 pA/pF through inhibiting process of I(Ca,T) activation. Furthermore, carvedilol delayed recovery from inactivation of I(Ca,T) and shortened the time constants of deactivation in HMI cells. This study suggested that the application of carvedilol in HMI cells contributes to the dynamic changes in I(Ca,T) and may account for reduction of incidence of arrhythmia after myocardial infarction.

The Association Between Smoking and Renal Function in People Over 20 Years Old.

Background: Many conclusions have been reached in renal function studies in direct smokers. Aim: This study aimed to determine the relationship between smoking and decreased renal function to ensure that reduced chronic kidney disease incidence can be achieved by limiting smoking, we assessed the relationship between cigarette smoking and renal function. Methods: We recruited 10,267 people from the National Health and Nutrition Program Testing Survey (NHANES) aged over 20 years from 2013 to 2018 to assess smoking exposure by serum cotinine. We estimated the glomerular filtration rate (eGFR) and used multivariate linear regression models and smooth curve fittings to assess the relationship between smoking and renal function. Results: We found an inverse relationship between serum cotinine and the eGFR. In a subgroup analysis, we found a non-linear relationship between serum cotinine and the eGFR in different ethnic groups or in different sexes. In a subgroup analysis of sex, we found inflection points between men and women for the relationship between serum cotinine and the eGFR (men 183 ng/ml and 465 ng/ml; women 227 ng/ml and 412 ng/ml). However, in a subgroup analysis by age, we found that serum cotinine showed a clear negative correlation with the eGFR in people aged 20-39 years, but in people older than 40 years, a weak correlation was shown. In stratified analysis by ethnicity, we found significant negative associations in Mexican American and Other Hispanic individuals and weaker associations in Non-Hispanic White and Non-Hispanic Black individuals. Conclusion: Through the negative correlation between serum cotinine and the eGFR, we can conclude that as the smoking quantity increases, smoking leads to a decrease in renal function. The results of the subgroup analysis indicate that in young people, by advocating smoking cessation early, we can very effectively prevent kidney disease in this population and thus reduce the incidence of chronic kidney disease. Smoking should be included as an independent risk factor for chronic kidney disease.

Noninvasive evaluation of hypoxia in rabbit VX2 lung transplant tumors using spectral CT parameters and texture analysis.

AIM: Noninvasive evaluation of hypoxia in rabbit VX2 lung transplant tumors using spectral CT parameters and texture analysis. MATERIALS AND METHODS: Twenty-five VX2 lung transplant tumors of twenty-two rabbits were included in the study. Contrast-enhanced spectral CT scanning in the arterial phase (AP) and venous phase (VP) was performed. Tumors were divided into strong and weak hypoxic groups by hypoxic probe staining results. Spectral CT image-related parameters [70 keV CT value, normalized iodine concentration (NIC), slope of spectral HU curve (λHU)] were measured and the texture analysis on the monochromatic images was performed. Imaging parameters and texture features between tumors with different hypoxic degrees were compared and their diagnostic efficacies for predicting hypoxia in lung cancers were analyzed using receiver operating characteristic (ROC) curve. RESULTS: NIC in VP and λHU in VP of the strong hypoxic group were significantly higher than those in the weak hypoxic group (p < 0.05). For the texture features, entropy in VP and kurtosis in AP were significantly different between the two hypoxic groups. According to ROC analysis, λHU in VP had a better diagnostic ability for predicting hypoxia in tumors [Area Under Curve (AUC): 0.883, sensitivity: 85.7%, specificity: 100%]. The combination of four features improved AUC to 0.955. CONCLUSION: NIC in VP, λHU in VP, entropy in VP and kurtosis in AP have certain values in predicting tumor hypoxia and a combination of image parameters and texture features improves diagnostic efficiency.

Cytokine storm and targeted therapy in hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome. The central pathogenesis is an explosive cytokine storm characterized by a significant increase in proinflammatory cytokines, including IL-1ß, IL-6, IL-18, IFN-γ, and TNF-α. Meanwhile, negative regulatory factors, such as IL-10 and TGF-ß, are also related to the production of HLH. Exploring the specific mechanism of cytokine storms could provide ideas regarding targeted therapy, which could be helpful for early treatment to reduce the mortality of HLH. Although some research has focused on the advantages of targeted therapies, there is still a lack of a comprehensive discourse. This article attempts to summarize the mechanisms of action of various cytokines and provide a therapeutic overview of the current targeted therapies for HLH.

[Spatial Differences in Water Quality and Spatial Autocorrelation Analysis of Eutrophication in Songhua Lake].

To identify the spatial differences in the water quality and eutrophication characteristics of Songhua Lake, the largest artificial lake in northeast China, analysis of variance (ANOVA) and factor analysis were used to analyze the water quality sampling and testing results in 2017 in three regions, namely the main reservoir area of the Fengman Reservoir (MRAFR), the experimental area of the Songhua River Three Lakes Protection Zone (EASRTLPZ), and the Jiaohe River backwater area (JRBA). The nutrient status of the lake was evaluated by the trophic state index method, and the spatial correlation and aggregation status of the eutrophication level in Songhua Lake were studied using spatial autocorrelation analysis. The main results were as follows: ① the ANOVA showed that, except for dissolved oxygen and chlorophyll-a (Chl-a), there were significant differences (P<0.05) in the total nitrogen (TN), total phosphorus (TP), water temperature (WT), and pH in the three areas of Songhua Lake, with the clearest difference between TN and TP. ② The factor analysis showed that the changes in the climatic condition factor (WT), nutrient salt factors (TN and TP), and algal biomass factor (Chl-a) dominated the water quality in the lake. ③ The results of the trophic state index showed that the nutrient status of Songhua Lake as a whole is mildly eutrophic, and the eutrophication levels of the three regions from strong to weak are JRBA > MRAFR > EASRTLPZ. ④ The global spatial autocorrelation showed that the eutrophication level of the lake as a whole has significant positive spatial autocorrelation owing to the influence of regional eutrophication levels. The spatial heterogeneity of the eutrophication level of Songhua Lake is low. ⑤ The results of the local spatial autocorrelation showed that the central and northern areas of JRBA are the hot spots (high/high concentration) of eutrophication in the lake (P<0.01), and the central part of EASRTLPZ is the cold spot (low/low concentration) of eutrophication in the lake (P<0.05). Therefore, when conducting water environmental management of Songhua Lake, the key areas for eutrophication control should be the JRBA and MRAFR.

[Primary studies on chemical constituents from butanol extraction of the thorny elaeagnus leaf and their cytotoxicity].

OBJECTIVE: To study the chemical constituents and test the cytotoxicity of the purified compounds from the Thorny Elaeagnus Leaf. METHODS: The constituents were isolated by column chromatography and their structures were elucidated by chemical properties and spectroscopic analysis. The cytotoxicity of the chemical components for SGC-7901 and Hela cells was measured by MuT method. RESULTS: Four components were isolated and identified as 3'-O-methylquercetin( 1),kaempferol-3-O-beta-D-6-O-(p-hydroxycinnamoyl) -glucopyranoside(2), kakkalide(3),3'-O-methyl-ellagic acid-4-O-alpha-L-rhamnicoside(4). These components had cytotoxicity for SGC-7901 and Hela cells. CONCLUSION: Compounds 1,3 and 4 are isolated from Thorny Elaeagnus Leaf for the first time. The results of pharmacological experiments indicate that compounds 1 and 2 show strong cytotoxicity to Hela cells.

Kv4.3 Modulates the Distribution of hERG.

This study examines the interaction between hERG and Kv4.3. The functional interaction between hERG and Kv4.3, expressed in a heterologous cell line, was studied using patch clamp techniques, western blot, immunofluorescence, and co-immunoprecipitation. Co-expression of Kv4.3 with hERG increased hERG current density (tail current after a step to +10 mV: 26 ± 3 versus 56 ± 7 pA/pF, p < 0.01). Kv4.3 co-expression also increased the protein expression and promoted the membrane localization of hERG. Western blot showed Kv4.3 increased hERG expression by Hsp70. hERG and Kv4.3 co-localized and co-immunoprecipitated in cultured 293 T cells, indicating physical interactions between hERG and Kv4.3 proteins in vitro. In addition, Hsp70 interacted with hERG and Kv4.3 respectively, and formed complexes with hERG and Kv4.3. The α subunit of Ito Kv4.3 can interact with and modify the localization of the α subunit of IKr hERG, thus providing potentially novel insights into the molecular mechanism of the malignant ventricular arrhythmia in heart failure.

Effects of allocryptopine on outward potassium current and slow delayed rectifier potassium current in rabbit myocardium.

OBJECTIVE: Allocryptopine (ALL) is an effective alkaloid of Corydalis decumbens (Thunb.) Pers. Papaveraceae and has proved to be anti-arrhythmic. The purpose of our study is to investigate the effects of ALL on transmural repolarizing ionic ingredients of outward potassium current (I to) and slow delayed rectifier potassium current (I Ks). METHODS: The monophasic action potential (MAP) technique was used to record the MAP duration of the epicardium (Epi), myocardium (M) and endocardium (Endo) of the rabbit heart and the whole cell patch clamp was used to record I to and I Ks in cardiomyocytes of Epi, M and Endo layers that were isolated from rabbit ventricles. RESULTS: The effects of ALL on MAP of Epi, M and Endo layers were disequilibrium. ALL could effectively reduce the transmural dispersion of repolarization (TDR) in rabbit transmural ventricular wall. ALL decreased the current densities of I to and I Ks in a voltage and concentration dependent way and narrowed the repolarizing differences among three layers. The analysis of gating kinetics showed ALL accelerated the channel activation of I to in M layers and partly inhibit the channel openings of I to in Epi, M and Endo cells. On the other hand, ALL mainly slowed channel deactivation of I Ks channel in Epi and Endo layers without affecting its activation. CONCLUSIONS: Our study gives partially explanation about the mechanisms of transmural inhibition of I to and I Ks channels by ALL in rabbit myocardium. These findings provide novel perspective regarding the anti-arrhythmogenesis application of ALL in clinical settings.

Effects of allitridum on the transient outward potassium current in rats with heart failure.

OBJECTIVE: To study the effect of allitridum on the transient outward potassium current (Ito) of ventricular myocytes in heart failure (HF). METHODS: The dual enzymatic method was used to separate single ventricular myocytes from Sprague Dawley rats. Patch-clamping was used to record Ito and analyze the effect of allitridum on the current. RESULTS: The Ito current had a significant decrease in the HF group, compared with the control group. The density of Ito in the HF group was increased after treatment of allitridum (30 µmol/L). The peak current densities of Ito were enhanced in the HF group from 6.01 ± 0.30 pA/pF to 8.41 ± 0.54 pA/pF (P < 0.01) at +50 mV after treatment with allitridum (30 µmol/L). We also determined the effect of allitridum on the gating mechanism of the Ito in the HF group. CONCLUSIONS: We found that allitridum increased the Ito by accelerating the activation of channels and shortened the time constants of inactivation, and allitridum decreased the remodeling of Ito in ventricular myocytes of rats with HF.

Characterization of a Chinese KCNQ1 mutation (R259H) that shortens repolarization and causes short QT syndrome 2.

OBJECTIVES: To evaluate the association between a KCNQ1 mutation, R259H, and short QT syndrome (SQTS) and to explore the electrophysiological mechanisms underlying their association. METHODS: We performed genetic screening of SQTS genes in 25 probands and their family members (63 patients). We used direct sequencing to screen the exons and intron-exon boundaries of candidate genes that encode ion channels which contribute to the repolarization of the ventricular action potential, including KCNQ1, KCNH2, KCNE1, KCNE2, KCNJ2, CACNA1c, CACNB2b and CACNA2D1. In one of the 25 SQTS probands screened, we discovered a KCNQ1 mutation, R259H. We cloned R259H and transiently expressed it in HEK-293 cells; then, currents were recorded using whole cell patch clamp techniques. RESULTS: R259H-KCNQ1 showed significantly increased current density, which was approximately 3-fold larger than that of wild type (WT) after a depolarizing pulse at 1 s. The steady state voltage dependence of the activation and inactivation did not show significant differences between the WT and R259H mutation (P > 0.05), whereas the time constant of deactivation was markedly prolonged in the mutant compared with the WT in terms of the test potentials, which indicated that the deactivation of R259H was markedly slower than that of the WT. These results suggested that the R259H mutation can effectively increase the slowly activated delayed rectifier potassium current (I Ks) in phase 3 of the cardiac action potential, which may be an infrequent cause of QT interval shortening. CONCLUSIONS: R259H is a gain-of-function mutation of the KCNQ1 channel that is responsible for SQTS2. This is the first time that the R259H mutation was detected in Chinese people.

[Effect of neurotrophin p75 receptor activation on transmural dispersion repolarization in rabbits with myocardial infarction].

OBJECTIVE: To elucidate the effect of neurotrophin p75 receptor (p75NTR)on transmural dispersion repolarization (TDR) of the layers of left ventricular myocytes in rabbits with myocardial infarction (MI). METHODS: Forty Japanese rabbits were divided into four groups (n = 10): (1) Sham group, (2) Heald myocardial infarction (HMI) group, (3) p75 NTR activation group, (4) p75 NTR inhibition group. Cardiomyocytes were isolated with enzyme digestion and the currents were recorded by whole-cell patch-clamp technique. RESULTS: Compared with those in the sham group, the duration of 90% action potential repolarization (APD90) and transmural dispersion repolarization of three layers of left ventricular myocytes were obviously raised (P < 0.05). But significant reduction was observed in p75NTR(-) group. Current densities of Ito and I(Ks, tail) in the p75NTR(+) group and HMI group were significantly reduced (P < 0.05), especially in mid myocytes. And no obvious changes were observed in p75NTR(-) group. CONCLUSION: Activation of p75NTR(+) increases transmural dispersion repolarization, which may lead to the incidence of arrhythmia.

Effects of nerve growth factor on the action potential duration and repolarizing currents in a rabbit model of myocardial infarction.

OBJECTIVES: To investigate the effect of nerve growth factor (NGF) on the action potential and potassium currents of non-infarcted myocardium in the myocardial infarcted rabbit model. METHODS: Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (healed myocardial infarction, HMI). During ligation surgery of the left coronary artery, a polyethylene tube was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/d for eight weeks (HMI + NGF group). Cardiomyocytes were isolated from regions of the non-infarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps. RESULTS: Compared with HMI and control cardiomyocytes, significant prolongation of APD50 or APD90 (Action potential duration (APD) measured at 50% and 90% of repolarization) in HMI + NGF cardiomyocytes was found. The results showed that the 4-aminopyridine sensitive transient outward potassium current (I to), the rapidly activated omponent of delayed rectifier potassium current (I Kr), the slowly activated component of delayed rectifier potassium current (I Ks), and the L-type calcium current (I CaL) were significantly altered in NGF + HMI cardiomyocytes compared with HMI and control cells. CONCLUSIONS: Our results suggest that NGF treatment significantly prolongs APD in HMI cardiomyocytes and that a decrease in outward potassium currents and an increase of inward Ca(2+) current are likely the underlying mechanism of action.

Hyperpolarization activated cation current (I(f)) in cardiac myocytes from pulmonary vein sleeves in the canine with atrial fibrillation.

OBJECTIVE: To investigate the characteristics of ectopic automaticity and cation current (I(f)) of cardiac myocytes from pulmonary vein sleeves (PVs) in canines with atrial fibrillation. METHODS: The canines (8-10 years old) were subjected to long-term, rapid atrial pacing (RAP) for 10 weeks, which induced the atrial fibrillation model. Disassociation of PVs of canines yielded single cardiac myocytes from a Landengorff column. Action potential, I(f) and hyperpolarisation activated cyclic nucleotide-gated (HCN) currents were measured with the patch-clamp technique. RESULTS: Compared with the control group, cardiac myocytes from the RAP canine PVs had spontaneous diastolic depolarization, shorter action potential duration, and larger I(f) densities. In the group of RAP cells, the half maximal activation potential (V(1/2)) was found to be less negative (-105.5 ± 5.2 mV) compared to control cells (-87.3 ± 4.9 mV). Current densities of I(f) were increased significantly by ß-adrenergic receptor stimulation with isoproterenol and caused an acceleration of current activation. In contrast, I(f) currents in the RAP were reduced by carvedilol, a selective beta-adrenergic receptor. Another important finding is that HCN4-based channels may make a significant contribution to I(f) in PVs cells, but not HCN2. Meanwhile, HCN4 current significantly increases in canine PVs cardiac myocytes with RAP. CONCLUSIONS: The spontaneous action potential and larger I(f) current were observed in the PVs cardiac myocytes using RAP, which may contribute to more ectopic activity events to trigger and maintain atrial fibrillation.