Atrial Natriuretic Peptide Levels Research Articles

Genetic variations in the transcription factors GATA4 and GATA6 and bleeding complications in patients receiving warfarin therapy.

Purpose: GATA4 and GATA6 are known to have potential roles in vascular regulation by affecting vascular smooth muscle cell differentiation and atrial natriuretic peptide levels. The aim of this retrospective study was to investigate the associations between GATA4 and GATA6 polymorphisms and bleeding complication risk at a therapeutic international normalized ratio (INR) in patients with mechanical heart valves.Patients and methods: Study patients were included from the Ewha-Severance Treatment (EAST) Group of Warfarin. It consisted of 229 patients who received warfarin therapy after undergoing mechanical heart valve replacement and maintained a stable INR (INR of 2.0–3.0 for at least three consecutive times). Twenty single-nucleotide polymorphisms including VKORC1, CYP2C9, GATA4, and GATA6 were analyzed. Multivariate logistic regression analysis was employed to investigate the independent risk factors for bleeding complications. To evaluate the potential clinical value of genotyping for preventing bleeding complications in patients with high-risk genotype, the number needed to genotype (NNG) was also calculated.Results: One hundred forty-two patients were included in this study, 21 of whom had bleeding complications. After adjusting covariates, TT genotype carriers of rs13273672 in GATA4 and CC genotype carriers of rs10454095 in GATA6 showed 5.0- (95% CI, 1.6–15.7) and 3.1-fold (95% CI, 1.1–8.7) higher bleeding complications than carriers of C allele and T allele, respectively. NNG for preventing one patient from experiencing bleeding complications in patients with TT genotype of rs13273672 and CC genotype of rs10454095 was 22.2 and 17.5, respectively. Patients with both TT genotype in rs13273672 and CC genotype in rs10454095 showed 8.7-fold (95% CI, 1.7–46.1) higher bleeding complications than those with other genotypes. NNG in patients having both TT genotype in rs13273672 and CC genotype in rs10454095 was calculated to be 40.0.Conclusions: This study showed that GATA4 and GATA6 gene polymorphisms could affect bleeding complications during warfarin treatment in patients with mechanical heart valves.

Aconitine ameliorates cardiomyocyte hypertrophy induced by angiotensin Ⅱ

This paper was aimed to investigate the inhibitory effect of aconitine(AC) on angiotensin Ⅱ(Ang Ⅱ)-induced H9 c2 cell hypertrophy and explore its mechanism of action. The model of hypertrophy was induced by Ang Ⅱ(1×10-6 mol·L-1),and cardiomyocytes were incubated with different concentrations of AC. Western blot was used to quantify the protein expression levels of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),β-myosin heavy chain(β-MHC),and α-smooth muscle actin(α-SMA). Real-time quantitative PCR(qRT-PCR) was used to quantify the mRNA expression levels of cardiac hypertrophic markers ANP,BNP and β-MHC. In addition,the fluorescence intensity of the F-actin marker,an important component of myofibrils,was detected by using laser confocal microscope. AC could significantly reverse the increase of total protein content in H9 c2 cells induced by Ang Ⅱ; qRT-PCR results showed that AC could significantly inhibit the ANP,BNP and β-MHC mRNA up-regulation induced by AngⅡ. Western blot results showed that AC could significantly inhibit the ANP,BNP and β-MHC protein up-regulation induced by AngⅡ. In addition,F-actin expression induced by Ang Ⅱ could be inhibited by AC,and multiple indicators of cardiomyocyte hypertrophy induced by Ang Ⅱ could be down-regulated,indicating that AC may inhibit cardiac hypertrophy by inhibiting the expression of hypertrophic factors,providing new clues for exploring the cardiovascular protection of AC.

Antihypertrophic Effects of Nebivolol on Neonatal Cardiomyocyte Hypertrophy Models.

The antihypertrophic effect of nebivolol over cardioselective beta-blockers (β-blockers) is attributed to the activation of cardiac nitric oxide signaling. However, the precise role of nebivolol on hypertrophied cardiomyocytes remains unclear. In the current study, in vitro cardiomyocyte hypertrophy model was induced with isoprenaline (10 μM), angiotensin II (1 μM), and phenylephrine (20 μM) in neonatal cardiomyocytes isolated from 0- to 2-day-old Sprague-Dawley rats. In addition to hypertrophic agents, cardiomyocytes were treated with nebivolol (1 μM), metoprolol (10 μM), N(ω)-nitro-L-arginine methyl ester (L-NAME) (100 μM), KT5823 (1 μM), DETA-NONOate (1-10 μM), and BAY412272 (10 μM). After 24 hours of treatment, cardiomyocyte size and transcriptional changes in cardiac hypertrophy markers were evaluated. Cardiomyocyte size increased equally in response to all hypertrophic agents. Nebivolol reduced the enhancement in cell size in response to both isoprenaline and angiotensin II; metoprolol did not. The antihypertrophic effect of nebivolol was prevented with L-NAME blockage indicating the role of NOS signaling on cardiomyocyte hypertrophy. The increased mRNA levels of atrial natriuretic peptide induced by isoprenaline decreased with nebivolol, but both β-blockers reduced the angiotensin II-induced increase in atrial natriuretic peptide expression. Combined, these results reveal that by activating NOS signaling, nebivolol exerts antihypertrophic effects on neonatal cardiomyocytes independent from the action mechanism of hypertrophic stimulus.

Simvastatin Improves Cardiac Hypertrophy in Diabetic Rats by Attenuation of Oxidative Stress and Inflammation Induced by Calpain-1-Mediated Activation of Nuclear Factor-κB (NF-κB).

BackgroundSimvastatin, an HMG-CoA reductase inhibitor, has been reported to exert multiple protective effects on the cardiovascular system. However, the molecular mechanism remains to be examined. The present study was designed to study the effects of simvastatin on cardiac hypertrophy in diabetic rats and to explore its potential mechanism.Material/MethodsSprague-Dawley rats were assigned into a control (Con) group, a streptozotocin (STZ) group, and a STZ+simvastatin (STZ+SIM) group. The level of reactive oxygen species (ROS) was measured by using dihydroethidium (DHE) staining. The protein expressions of p65, IκBα, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), calpain-1, and endothelial nitric oxide synthase (eNOS) were examined by Western blot analysis. qPCR was used to detect the levels of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP).ResultsSimvastatin improved the cardiac hypertrophy of diabetic rats, as demonstrated by decreases in the ratios of left ventricular weight/body weight (LVW/BW) and heart weight/body weight (HW/BW) and by the downregulation of mRNA expression of BNP and ANP in the heart tissue. Simvastatin decreased the protein expressions of VCAM-1, ICAM-1, IL-6, and TNF-α, increased eNOS protein expression, and limited an increase in ROS levels in the heart tissue. Simvastatin increased IκBα protein expression in cytoplasm and inhibited the translocation of p65, the subunit of nuclear factor-κB (NF-κB) to the nucleus from the cytoplasm of the heart tissue. Furthermore, simvastatin attenuated the activity of calpain and calpain-1 protein expression in heart tissue.ConclusionsSimvastatin attenuates cardiac hypertrophy in diabetic rats, which might be due to the attenuation of oxidative stress and inflammation induced by calpain-1-mediated activation of NF-κB.

Detection of oxytocin, atrial natriuretic peptide, and brain natriuretic peptide using novel imprinted polymers produced with amphiphilic monomers.

The cystine-bridged cyclic peptide hormones (CBCPHs) represent signature structural feature as well as unique biological activity. In this study, three CBCPHs have been identified and characterized, namely, oxytocin, atrial natriuretic peptides (ANPs), and brain natriuretic peptides (BNPs). Because research has shown that ANPs and BNPs are powerful diagnostic biomarkers for heart disease, a highly laudable endeavor would be to develop a novel sensor for detecting ANP or BNP levels. Therefore, an amphiphilic monomer Acr-His-NHNH-Fmoc was synthesized to form molecularly imprinted polymers (MIPs) for targeted CBCPH detection. First, oxytocin, a cardiovascular hormone and a CBCPH, was used as a template to fabricate MIPs on quartz crystal microbalance (QCM) chips. On the other hand, fabricated selected ANP segment or BNP segment as an epitope is able to construct epitope-mediated MIPs (EMIPs) for ANP or BNP. The developed oxytocin or ANP sensor reached a detection limitation of 0.1nM with the dissociation constants being 30pM for oxytocin and 20pM for ANP. Moreover, BNP sensor achieved a detection limitation of 2.89pM with an even lower Kd value as 2pM. Compared with the performance of EMIPs, the imprinted films showed high affinity and selectivity in special binding to CBCPHs. The developed MIPs-QCM biosensors thus provide an improved sensing platform using an amphiphilic monomer and may be useful for applications toward cyclotides, cystine knot motifs, or insulin-like peptides.

Right ventricular remodeling in response to volume overload in fetal sheep.

The fetal myocardium is known to be sensitive to hemodynamic load, responding to systolic overload with cellular hypertrophy, proliferation, and accelerated maturation. However, the fetal cardiac growth response to primary volume overload is unknown. We hypothesized that increased venous return would stimulate fetal cardiomyocyte proliferation and terminal differentiation, particularly in the right ventricle (RV). Vascular catheters and pulmonary artery flow probes were implanted in 16 late-gestation fetal sheep: a right carotid artery-jugular vein (AV) fistula was surgically created in nine fetuses, and sham operations were performed on seven fetuses. Instrumented fetuses were studied for 1 wk before hearts were dissected for component analysis or cardiomyocyte dispersion for cellular measurements. Within 1 day of AV fistula creation, RV output was 20% higher in experimental than sham fetuses ( P < 0.0001). Circulating atrial natriuretic peptide levels were elevated fivefold in fetuses with an AV fistula ( P < 0.002). On the terminal day, RV-to-body weight ratios were 35% higher in the AV fistula group ( P < 0.05). Both left ventricular and RV cardiomyocytes grew longer in fetuses with an AV fistula ( P < 0.02). Cell cycle activity was depressed by >50% [significant in left ventricle ( P < 0.02), but not RV ( P < 0.054)]. Rates of terminal differentiation were unchanged. Based on these studies, we speculate that atrial natriuretic peptide suppressed fetal cardiomyocyte cell cycle activity. Unlike systolic overload, fetal diastolic load appears to drive myocyte enlargement, but not cardiomyocyte proliferation or maturation. These changes could predispose to RV dysfunction later in life. NEW & NOTEWORTHY Adaptation of the fetal heart to changes in cardiac load allows the fetus to maintain adequate blood flow to its systemic and placental circulations, which is necessary for the well-being of the fetus. Addition of arterial-venous fistula flow to existing venous return increased right ventricular stroke volume and output. The fetal heart compensated by cardiomyocyte elongation without accelerated cellular maturation, while cardiomyocyte proliferation decreased. Even transient volume overload in utero alters myocardial structure and cardiomyocyte endowment.

Potential and Limitations of Atrial Natriuretic Peptide as Biomarker in Pediatric Heart Failure-A Comparative Review.

Although B-type Natriuretic Peptide (BNP), N-terminal-proBNP (NT-proBNP), and mid-regional-proANP (MR-proANP) are included in current guidelines on heart failure in adults, no guideline considering these biomarkers in pediatric heart failure is available. A new drug class of neprilysin inhibitors as fixed-dose combination (Sacubitril/valsartan) has been introduced and is currently being investigated in children suffering from heart failure. Atrial Natriuretic Peptide (ANP) is discussed as a more useful alternative to BNP because it may grants better insights into the effects of this treatment. Thus, this review aimed to provide an overview of the current knowledge concerning ANP in pediatric heart failure and compares its suitability regarding diagnosis and prognosis of heart failure. A literature search using PubMed resulted in 147 publications of which 22 studies were classified as relevant. The review presents available ANP, NT-proANP, and MR-proANP level data in children (0–18 years). Summarizing, ANP shows only minor differences as marker for diagnosing and monitoring pediatric heart failure if compared to BNP. Due to its fast release, ANP offers the advantage of displaying rapid changes during therapy or operation. ANP is -like the other natriuretic peptides- influenced by age, presenting with the highest levels in very young infants. ANP also correlates with atrial pressure and volume overload in children. In addition, ANP determination in saliva appears to be a promising alternative to blood sampling. Similarly to NT-proBNP, NT-proANP, and MR-proANP offer better stability but only few data has been published in children and thus their potential is only presumable so far.

Down-regulation of miR-200c attenuates AngII-induced cardiac hypertrophy via targeting the MLCK-mediated pathway.

BackgroundMicroRNAs (miRNAs) have been shown to commonly contribute to cardiac hypertrophy (CH). The aim of this study was to test the hypothesis that miR‐200c plays an important role in the progression of CH by targeting myosin light chain kinase (MLCK/MYLK).Methods and resultsCardiac hypertrophy was induced by aortic banding (AB) in rats. Cellular hypertrophy in neonatal rat cardiomyocytes (NCMs) was induced by AngII treatment. Echocardiography, histology and molecular measurements were used to assess the results of the experiments. The levels of apoptosis and reactive oxygen species (ROS) were also measured. Quantitative real‐time PCR (qRT‐PCR) and Western blotting were used to measure mRNA and protein levels respectively. The present results showed that miR‐200c expression was increased in response to CH both in vivo and in vitro. The down‐regulation of miRNA‐200c by a specific inhibitor markedly ameliorated CH resulting from AngII treatment, and the mRNA levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain were simultaneously decreased. Notably, minimal apoptosis and ROS accumulation were identified in AngII‐induced hypertrophic cardiomyocytes. Conversely, the up‐regulation of miR‐200c using specific mimics reversed these effects. Mechanistic investigations demonstrated that the MLCK gene is a direct target of miR‐200c; an increase in miR‐200c levels led to a decrease in the expression of MLCK and its downstream effector, p‐MLC2, while miR‐200c inhibition increased the expression of these proteins. Furthermore, inhibiting MLCK impaired the anti‐hypertrophic effects contributions produced by the knockdown of miR‐200c.ConclusionOur studies suggest that miR‐200c may serve as a potential therapeutic target that could delay hypertrophy. We have also uncovered a relationship between miR‐200c and MLCK, identifying MLCK as a direct mediator of miR‐200c.

The relationship between atrial natriuretic peptide and microvascular complications of diabetes

Objective: In this study, we aimed to determine the relationship between the atrial natriuretic peptide and microvascular complications of diabetes. Methods: Sixty patients with type 2 diabetes mellitus were enrolled into the study. Patients with a chronic disease other than diabetes mellitus were excluded from the study. The body-mass index, waist circumference, and hip circumference were measured and blood samples for routine biochemical tests were taken after at least 12 hours fasting. The microvascular complications of the patients were evaluated. Results: Thirty-two of the patients had microvascular complications whereas 28 of them did not. Age, body mass index, waist and hip circumference, and atrial natriuretic peptide levels were significantly higher in the group with microvascular complications than those without complications. There was no significant difference in parameters like; waist-hip ratio, blood glucose, HbA1c, fasting insulin, fasting HOMA, sodium, potassium, magnesium, calcium and lipid levels between the two groups. When the relationship between atrial natriuretic peptide and obesity, retinopathy, neuropathy, nephropathy, duration of diabetes, HbA1c, and sex are evaluated separately, the only significant parameters related to atrial natriuretic peptide were the body-mass index, waist circumference, hip circumference measurements, and neuropathy. Conclusions: Positive correlations between serum atrial natriuretic peptide levels and body-mass index, waist circumference, and hip circumference measurements were determined. Also, serum atrial natriuretic peptide levels were significantly higher in patients with obesity or neuropathy than those without obesity or neuropathy.

Ионорегулирующая функция почек и эффект глюкагоноподобного пептида-1 у крыс на высокосолевой диете

Glucagon-like peptide-1 (GLP-1) is the main incretin hormone that has an insulinotropic effect after a meal, as well as a physiologically significant natriuretic factor that contributes to the regulation of sodium and water balance. The aim of the work is to evaluate the effect of GLP-1 and its mimetic on the ion-regulating function of the kidneys in rats that are kept on a diet with a high concentration of NaCl for a long time, as well as in experimental hypervolemia and hypernatremia. In Wistar rats that received feed with a high content of NaCl (4%) for a month compared to animals on a standard diet (0.4% NaCl) the levels of blood pressure and atrial natriuretic peptide did not change, the aldosterone concentration in the blood decreased, the urinary excretion of sodium, calcium and chloride ions increased. After the administration of glucagon-like peptide-1 (GLP-1) and its mimetic, exenatide, the excretion of sodium ions and chlorides by the kidneys increased, the magnitude of natriuresis was equal in rats with different levels of NaCl intake with feed, that indicates the independence of the natriuretic action of GLP-1 from the excess of NaCl in the body due to the long-term high salt intake. In contrast to the standard diet, on high-salt feed, a lower level of aldosterone in the blood of rats caused a lower loss of potassium in the urine under the action of GLP-1 and exenatide. Similar changes in the urinary sodium and potassium excretion were observed under the action of GLP-1 mimetic in rats with hypervolemia caused by intraperitoneal administration of isotonic NaCl solution. A summation of the effects of exenatide and a loading test on the excretion of sodium was observed in rats with hypernatremia after administration of hypertonic solution of NaCl. Thus, GLP-1 is an effective natriuretic factor, both under standard conditions of water-salt balance, as well as with acute and chronic excess of NaCl in the body.

Green peas protein hydrolyzed by bromelain in simple procedure to improve kidney function in cisplatin-induced rats

Context: Chronic kidney disease (CKD) can lead to terminal kidney failure. Previous study has shown that protein hydrolysate in yellow peas (Pisum sativum L.) can be used as a natural remedy for CKD. Aims: To obtain hydrolysate protein that is most effective in improving kidney function of cisplatin (CP)-induced Wistar rats, based on urea, creatinine, atrial natriuretic peptide (ANP), cyclooxygenase-1 (COX-1), and renin levels of CP-induced nephrotoxicity Wistar rats. Materials and Methods: Methods of Kjeldahl, Bradford, Kunitz, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were used to determine the content of the eight types of protein hydrolysates. In in vivo experiment, the samples were administered to CP-induced nephrotoxicity Wistar rats, with urea, creatinine, ANP, COX-1, and renin as parameters. Results: Total neutrase activity was 40.65 U/mg, and bromelain was 35.77 U/mg. Total specific activities of both enzymes were almost identical. Protein hydrolyzed using bromelain had small fractions (<14.4 kDa). On the 30th day of treatment, urea and creatinine levels of all groups of treatment were significantly different from CP control (P < 0.01). The lowest level was shown by the group which was treated with bromelain-hydrolyzed green pea protein. Among ANP, COX-1, and renin measurements, only the result of COX-1 showed the promising result. Conclusions: Green peas protein hydrolysate hydrolyzed by bromelain are suggested as the most effective in improving kidney function based on urea, creatinine, and COX-1 levels of CP-induced nephrotoxicity Wistar rats.

Effect of chloroquine treatment on cardiac function as well as cardiac atrial natriuretic peptide level in Bcl-2-associated athanogene (BAG) 3 transgenic mice

Effect of chloroquine treatment on cardiac function as well as cardiac atrial natriuretic peptide level in Bcl-2-associated athanogene (BAG) 3 transgenic mice

Twenty-Four-Hour Blood Pressure-Lowering Effect of a Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Diabetes and Uncontrolled Nocturnal Hypertension: Results From the Randomized, Placebo-Controlled SACRA Study.

The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m2). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (-6.3 mm Hg; P=0.004); between-group difference in change from baseline was -4.3 mm Hg (P=0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (-9.5, -7.7, -7.5, and -8.6 mm Hg, respectively; all P≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (-1.3 kg and -0.33%; both P<0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (-12.1%; P=0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (-8.2% [P=0.008] and -9.7% [P=0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. URL: https://www. gov. Unique identifier: NCT03050229.

Comparison of effects of MHBFC on cardiac hypertrophy after banding of the abdominal aorta in wild-type mice and eNOS knockout mice

17-Methoxyl-7-hydroxy-benzene-furanchalcone (MHBFC) was isolated from the Millettia pulchra (Benth.) Kurz var. Laxior (Dunn) Z. Wei (Papilionaceae) (MKL) roots. This study aimed to study the effects of MHBFC on cardiac hypertrophy after banding of the abdominal aorta in wild-type mice and endothelial nitric oxide synthase (eNOS) knockout mice in order to verify whether MHBFC depends on the eNOS gene in reversing cardiac hypertrophy. By observing the blood pressure, body weight, ventricular hypertrophy index, expression of B-type natriuretic peptide (BNP), myosin heavy chain beta (β-MHC), atrial natriuretic peptide (ANP), serum amyloid A SAA mRNA, level of endothelin-1 (ET-1) protein, histopathological changes of myocardial cells, and the myocardial ultrastructure, we found that MHBFC significantly ameliorated the changes in the structure of the heart and aorta, significantly decreased the blood pressure, myocardial cell cross-section area, level of ET-1 protein, and mRNA levels of BNP, β-MHC, ANP and SAA, prevented myocardial ultrastructure alterations, and relieved myocardial and perivascular fibrosis of wild-type mice. However, MHBFC could not induce any significant change in eNOS gene knockout mice. These results show that MHBFC is beneficial to protect against cardiac hypertrophy after banding of the abdominal aorta in wild-type mice, but has no such effect on eNOS gene knockout mice, which indicates that MHBFC is dependent on the existence of the eNOS gene in reversing cardiac hypertrophy.

Chronic inhibition of nitric oxide synthase modulates calcium handling in rat heart 1.

Systemic infusion of nitric oxide synthase (NOS) inhibitors increases peripheral vascular resistance due to inhibition of endothelial NOS leading to the activation of the arterial baroreceptor mechanisms and inhibition of central sympathetic outflow. In the current study, we explored that systemic NOS blockage activates protein kinase A (PKA)-mediated signaling pathway through maintained cGMP-dependent protein kinase (PKG) activation. Rats were treated with 3 different concentrations of N(ω)-nitro-l-arginine methyl ester (L-NAME) for 14 days. Systemic L-NAME treatment induced a dose-dependent increase in blood pressure and increased mRNA levels of atrial natriuretic peptide (ANP) and phosphorylation levels of p44/42 MAPK without any change in cardiac mass. The cardiac cGMP levels and PKG-mediated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) (Ser239) did not alter in any group. At the highest dose of treatment (100 mg/kg per day), PKA-mediated phosphorylations of VASP (Ser157) and troponin I (TnI) (Ser23/24) were enhanced significantly indicating the increase in PKA activation in response to chronic NOS blockage. Alterations in both phosphorylated phospholamban (Ser16/Thr17) and sarcoplasmic/endoplasmic Ca2+-ATPase (SERCA2) levels can increase cytosolic Ca2+ load and impair Ca2+ handling. Our data suggest that the increased PKA activation in response to chronic NOS blockage appears to be responsible for cardiac abnormalities that occur due to prolonged L-NAME treatment.

Major depression and atrial natriuretic peptide: The role of adverse childhood experiences

Atrial natriuretic peptide (ANP) exerts anxiolytic effects in animals and humans. Patients with anxiety, trauma-associated and depressive disorders exhibit lower ANP plasma levels compared to healthy individuals. However, the role of ANP in patients with major depressive disorder (MDD) with and without concomitant adverse childhood experiences (ACE) and in healthy individuals with and without ACE is not clear.We recruited a total of 93 women: 23 women with MDD and ACE, 24 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD, and 24 healthy women without ACE. ANP plasma levels were measured with a radioimmunoassay.The four groups did not differ in demographic and clinical variables. We found a positive correlation between age and plasma levels of ANP (r = .39; p < .001). After controlling for age, there was no significant main effect of MDD or ACE on ANP plasma levels, but a significant interaction between MDD and ACE such that ACE was associated with reduced basal ANP levels in the absence of MDD.We assume that low plasma ANP might be a consequence of ACE in the absence of current psychopathology. Therefore, future studies are needed to replicate our findings and to characterize the influencing factors of ACE on ANP more comprehensively, for example by including a comprehensive trauma and comorbidity anamnesis as well as cardiovascular state and risk factors.

San-Ao Decoction () Regulates Urine Volume on Bronchial Asthma Model Mice.

To observe the effect of San-Ao Decoction (, SAD) on water metabolism of bronchial asthra model mice. Forty-five female BALB/c mice were randomly divided into control, model and SAD groups by a random number table, 15 mice in each group. A composite method with ovalbumin (OVA) sensitization and challenge was developed to establish bronchial asthma model. Mice in the control group were intraperitoneally injected with distilled water without aerosol inhalation challenge. On day 15-22, 0.3 mL SAD was administered via gastric route in SAD group, one time per day, while an equivalent volume of normal saline was used for gastric administration in the control and model groups. Changes in airway resistance in the inspiratory phase (RI-R-Area) were detected using an AniRes2005 system, and 5-h urine output was collected by metabolic cages. Histopathological changes in lung and kidney were observed by hematoxylin-eosin staining. mRNA expressions of aquaporin (AQP) 1 and AQP2 in kidney were detected by reverse transcription-polymerase chain reaction, and the protein expressions of AQP1 and AQP2 in kidney were detected by immunohistochemistry. Enzyme-linked immune sorbent assay was used to detect the OVA-specific endothelium-1 (ET-1), antidiuretic hormone (ADH), atrial natriuretic peptide (ANP), prostaglandin E2 (PGE2), and angiotensin II (Ang II) levels in serum, lung and kidney tissues, respectively. The nitric oxide (NO) contents in serum, lung, and kidney tissues were tested by chemical method, respectively. Compared with the control group, the serum IgE level in model group increased (P<0.01). Following the pathologic changes in lung tissue, no significant change in kidney tissue was observed among 3 groups. Compared with the control group, the mice in the model group showed elevated airway resistance during inhalation phase, higher mRNA and protein expression levels on AQP1 and AQP2 in kidney tissue and higher ET-1 levels in serum, lung and kidney tissues, ADH and ANP in lung and serum, PGE2 in kidney, Ang II in lung and kidney tissues (P<0.05 or P<0.01), but decreased in 5-h urinary output as well as NO and PGE2 contents in serum and lung tissues (P<0.05 or P<0.01). Compared with the model group, the mice in the SAD group showed a weakened airway resistance in inspiratory phase, lower mRNA and protein expressions of AQP1 and AQP2 in kidney tissues, lower levels of ET-1, ADH, ANP in serum as well as ET-1, ANP, Ang II levels in kidney tissues (P<0.05 or P<0.01), whereas 5-h urinary output, NO content in kidney, ADH, ANP and PGE2 levels in lung and Ang II in serum increased (P<0.05 or P<0.01). San-Ao Decoction can regulate the urine volume through regulating AQP1 and AQP2 expression, and the expression of these in the kidneys might be regulated by ET-1, NO and Ang II.

Apigenin-induced HIF-1α inhibitory effect improves abnormal glucolipid metabolism in AngⅡ/hypoxia-stimulated or HIF-1α-overexpressed H9c2 cells

BackgroundApigenin, a natural flavonoid compound, can improve the myocardial abnormal glucolipid metabolism and down-regulate the myocardial hypoxia inducible factor-1α (HIF-1α) in hypertensive cardiac hypertrophic rats. However, whether or not the ameliorative effect of glucolipid metabolism is from the reduction of HIF-1α expression remains uncertain. PurposeThis study aimed to investigate the exact relationship between them in angiotensin Ⅱ (Ang Ⅱ)/hypoxia-stimulated or HIF-1α overexpressed H9c2 cells. MethodsTwo cell models with Ang Ⅱ/hypoxia-induced hypertrophy and HIF-1α overexpression were established. After treatment of the cells with different concentrations of apigenin, the levels of total protein, free fatty acids (FFA), and glucose were detected by the colorimetric method, the level of atrial natriuretic peptide (ANP) was detected by the ELISA method, and the expressions of HIF-1α, peroxisome proliferator-activated receptor α/γ (PPARα/γ), carnitine palmitoyltmnsferase-1 (CPT-1), pyruvate dehydrogenase kinase-4 (PDK-4), glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter-4 (GLUT-4) proteins were detected by the Western blot assay. ResultsFollowing treatment of the both model cells with apigenin 1–10 μM for 24 h, the levels of intracellular total protein, ANP, and FFA were decreased, while the level of cultured supernatant glucose was increased. Importantly, apigenin treatment could inhibit the expressions of HIF-1α, PPARγ, GPAT, and GLUT-4 proteins, and increase the expressions of PPARα, CPT-1, and PDK-4 proteins. ConclusionApigenin could exert an ameliorative effect on abnormal glucolipid metabolism in AngⅡ/hypoxia-stimulated or HIF-1α-overexpressed H9c2 cells, and its mechanisms were associated with the inhibition of HIF-1α expression and subsequent upregulation of PPARα-mediated CPT-1 and PDK-4 expressions and downregulation of PPARγ-mediated GPAT and GLUT-4 expressions.

Dimethyl fumarate interferes with MyD88-dependent toll-like receptor signalling pathway in isoproterenol-induced cardiac hypertrophy model.

To investigate the effect of dimethyl fumarate (DMF) on Toll-like receptor (TLR) signalling pathway in isoproterenol (ISO)-induced cardiac hypertrophy in rats. Sixty adult male Sprague-Dawley rats were randomly allocated into three groups. group I: rats received the vehicles only; group II: rats were treated with ISO (5 mg/kg per day S.C.) to induce cardiac hypertrophy for 7 days; and group III: rats were given DMF (25 mg/kg per 12 h P.O.) for 28 days, and at the last 7 days, they were treated with ISO (5 mg/kg per day S.C.). Pretreatment with DMF decreased heart-to-body weight ratio, heart rate and blood pressure and improved the electrocardiographic patterns when compared with ISO group. DMF exhibited cardioprotective effect as evidenced by the reduction in cardiac troponin I, creatine kinase-MB and atrial natriuretic peptide levels. Moreover, DMF alleviated the changed oxidative stress and inflammatory biochemical markers through its anti-inflammatory and antioxidant effects. DMF interfered with TLR signalling pathway, evidenced by decreased levels of the TLR adaptor protein MyD88 and p-ERK1/2 and increased p-Akt level. Dimethyl fumarate exerted cardioprotective effect against ISO-induced cardiac hypertrophy. This effect is suggested to be through interfering with TLR signalling pathway.

Effects of dual angiotensin type 1 receptor/neprilysin inhibition vs. angiotensin type 1 receptor inhibition on target organ injury in the stroke-prone spontaneously hypertensive rat.

The combination of AT1 blocker/neutroendopeptidase neprilysin inhibition (ARNi) represents an interesting approach to reduce cardiovascular risk in hypertension. We assessed the efficacy of ARNi, compared with angiotensin II type 1 receptor blockade alone, on blood pressure (BP) and on protection from target organ damage development in the stroke-prone spontaneously hypertensive rat (SHRSP). In high-salt fed SHRSP, we assessed plasma and tissue natriuretic peptides, urinary volume, BP and body weight over a short-term treatment (6 weeks) with either ARNi (sacubitril/valsartan 68 mg/kg per day) or valsartan (30 mg/kg per day), protection from stroke and renal damage (as documented by proteinuria) over 4 months of treatment with either sacubitril/valsartan or valsartan; the ability of either treatment to reduce progression of cerebrovascular and renal damage after 2 weeks of high-salt diet. Higher levels of plasma and tissue atrial natriuretic peptide, of urinary cyclic guanosine 3'5'monophosphate and urine volumes, along with lower BP levels, were found upon sacubitril/valsartan as compared with valsartan over the short-term treatment. Sacubitril/valsartan caused a significant reduction of both BP and proteinuria levels and complete prevention of stroke over the long-term treatment. Once organ damage was established, a significant delay of its progression was observed with sacubitril/valsartan. The dual angiotensin II type 1 receptor/neutroendopeptidase inhibition significantly increased atrial natriuretic peptide level and reduced BP. Complete prevention of stroke was achieved in this model. The ability of sacubitril/valsartan to reduce organ damage progression was superior to that of valsartan alone. ARNi may represent a highly effective therapeutic agent to protect from target organ damage development in hypertension.