Atrial Natriuretic Peptide Concentrations Research Articles

Angiotensin Receptor-Neprilysin Inhibitor Suppresses Renin-Angiotensin-Aldosterone System Activation After Cardiac Surgery Using Cardiopulmonary Bypass.

Sacubitril/valsartan, being both a neprilysin inhibitor and angiotensin receptor blocker, exhibits a renin-angiotensin-aldosterone system (RAAS) inhibitory effect. However, no study has investigated the administration of sacubitril/valsartan in patients early after surgery using cardiopulmonary bypass.Methods and Results: This was a prospective observational study of 63 patients who underwent open heart surgery and were treated with sacubitril/valsartan. No serious adverse events occurred. Among the 63 patients, sacubitril/valsartan was discontinued in 13 due to hypotension (n=10), renal dysfunction (n=2), and dizziness (n=1). Atrial natriuretic peptide concentrations increased significantly from Day 3 of treatment (P=0.0142 vs. Postoperative Day 1) and remained high thereafter. In contrast, plasma renin activity was significantly suppressed from Day 3 onwards (P=0.00206 vs. Postoperative Day 1). A decrease in creatinine concentrations and an increase in the estimated glomerular filtration rate were observed on Day 3; this improvement in renal function was not observed in the historical control group, in which patients did not receive sacubitril/valsartan. New postoperative atrial fibrillation was less frequent in the study group compared with the historical control (12.7% vs. 38.0%; P=0.0034). Sacubitril/valsartan administration was safe immediately after open heart surgery in patients without postoperative hypotension. It enhanced serum atrial natriuretic peptide concentrations and suppressed RAAS activation.

The impact of GLP-1 receptor agonist liraglutide on blood pressure profile, hydration, natriuresis in diabetic patients with severely impaired kidney function

Chronic treatment with GLP-1R agonists may moderately lower blood pressure due to increased natriuresis and RAAS inhibition. Short-term effect of these drugs on blood pressure may be opposite and its mechanism remains unclear. We investigated the effect of a single dose of liraglutide on diurnal blood pressure profile, natriuresis, hydration and serum concentration of renin, aldosterone and atrial natriuretic peptide (ANP) in diabetic kidney disease (DKD). 17 patients with eGFR < 30 ml/min/1.73 m2 and 17 with > 60 ml/min/1.73 m2 received in a random order a single subcutaneous dose 1.2 mg liraglutide and placebo with subsequent 24 h blood pressure and natriuresis monitoring. Before and after each medication thoracic fluid index and plasma renin, aldosterone and ANP were also assessed. The blood pressure load in the daytime and nighttime were significantly increased after liraglutide compared to placebo in patients with eGFR < 30 ml/min/1.73 m2. In patients with eGFR > 60 ml/min/1.73 m2 the changes of arterial pressure were comparable, while the morning surge was significantly reduced after liraglutide compared to placebo. After liraglutide 24 h urine sodium excretion increased in both groups vs. placebo (p < 0.001), the effect was greatest in subjects with eGFR > 60 ml/min/1.73 m2. Plasma ANP increased after liraglutide in both groups, most in patients with eGFR < 30 ml/min/1.73 m2 group. Plasma aldosterone (p = 0.013) and thoracic fluid index (p = 0.01) decreased after liraglutide compared to placebo (p = 0.013 and p + 0.01, respectively. Plasma renin concentration remained unchanged. In severe chronic kidney disease liraglutide induces a transient increase of blood pressure due to reduced natriuresis. The natriuretic effect of liraglutide in DKD may be related to increased ANP and decreased aldosterone secretion.

Cyanidin prevents cardiomyocyte apoptosis in mice after myocardial infarction.

Myocardial infarction is a worldwide disease with high morbidity and mortality and a major cause of chronic heart failure, seriously affecting patients' quality of life. Natural medicine has been used to cure or prevent cardiovascular disease for decades. As a natural flavonoid, anthocyanidin has been used to treat many diseases due to its antioxidative, anti-inflammatory, and other properties. A mouse model (C57BL/6) weighing 30-40g was utilized to induce myocardial infarction by ligating the left anterior descending coronary artery. Cyanidin (30mg/kg) was administered orally to mice for four weeks. A variety of assessments were used to evaluate cardiac function. The gene expression was measured using RNAseq and Western blot. Histological changes in myocardial tissue were assessed using staining techniques, including Masson, Hematoxylin Eosin (HE), and transmission electron microscopy. Tunnel staining was implemented as a method to detect cellular apoptosis. For the quantification of B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in the serum, an enzyme-linked immunosorbent assay (ELISA) was employed. Furthermore, autodock simulation was executed in order to assess the interaction between cyanidin and a subset of genes. Cyanidin treatment inhibited myocardial cell apoptosis, improved cardiac function, and reduced serum concentrations of BNP and atrial natriuretic peptide ANP, as well as mitigated histological cardiac tissue damage. Cyanidin also inhibited the activity of matrix metalloproteinases (MMP2/9) and Fibronectin 1 (Fn1). Cyanidin improves heart function and reduces myocardial damage in mice after MI. Furthermore, cyanidin can prevent cardiomyocyte apoptosis. These effects are most likely caused by suppression of MMP9/2 and control of the Akt signaling pathway, suggesting an appropriate therapeutic target.

Studying the possibilities of pharmacological correction of hypoxia-induced pulmonary hypertension using a phenolic compound with a laboratory cypher KUD975

The aim of our work was to study a pharmacological activity of a selective arginase-2 and thrombin inhibitor from a phenolic compounds group with a laboratory cypher KUD975 on a model of arterial pulmonary hypertension induced by hypoxia.Materials and methods. To simulate pulmonary hypertension (РН), animals were placed in a normobaric hypoxic chamber and subjected to 5 weeks of hypoxia with an oxygen content of 10% in the air. After 3 weeks of hypoxia, the animals were administered with the test compound KUD975 (intragastrically, at a dose of 2 mg/kg once a day for 2 weeks). L-norvaline (intragastrically, 20 mg/kg) was used as a reference drug. To assess the development and correction of РН, measurements of cardiohemodynamics, analysis of blood gas composition, study of the number of circulating endothelial precursor cells (EPCs), quantitative PCR assessing the expression of mRNA VEGF-R2, SGF-1 (stromal growth factor-1) and MCP-1 (monocyte chemoattractant protein-1). Next, a histological examination of the lungs and heart was performed, the degree of pulmonary edema and the concentration of cardiotrophin-1 and atrial natriuretic peptide were assessed.Results. The administration of the studied phenolic compound with laboratory cypher KUD975, as well as the reference drug L-norvaline, led to a decrease in the right ventricular systolic pressure against the background of modeling РН. The present study shows a more than twice-fold decrease in the number of circulating (EPCs) in the animals group with modeling a hypoxia-induced circulatory РН (171.3±12.1) in comparison with the group of intact animals (296.1±31.7; p=0.0018). The recovery of EPCs was noted in the animals group administered with KUD-975 and L-norvaline, up to 247.5±34.2 (p=0.0009 compared with a pulmonary arterial hypertension (PAH) and 235.6±36.4 (p=0.008 compared to PAH), respectively. The studied compounds had a protective effect by statistically significantly increasing the expression of VEGF-R2 mRNA and decreasing the expression of SGF-1 mRNA, reducing the lung moisture coefficient and the concentrations of cardiotrophin-1 and atrial natriuretic peptide and preventing vascular remodeling caused by hypoxia.Conclusion. When studying the pharmacological activity, it was shown that the phenolic compound with the laboratory cypher KUD975 normalizes hemodynamic parameters, reduces the signs of remodeling of the heart and pulmonary vessels and has a pronounced endothelial protective effect on the model of hypoxia-induced РН, and is superior to the activity of the reference drug L-norvaline.

The impact of COVID-19 on BNP, NT-proBNP and ANP in heart failure.

Extensive research has been conducted on biomarkers associated with coronavirus disease 2019 (COVID-19) in both healthy individuals and those with various conditions, particularly heart diseases. However, there is a limited investigation into the relationship between widely used cardiac biomarkers known as natriuretic peptides, including Brain natriuretic peptide (BNP), N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and Atrial natriuretic peptide (ANP), and COVID-19 infection specifically in patients with heart failure. These natriuretic peptides assess the hemodynamic stress on the heart wall and have the potential to serve as biomarkers for evaluating the severity of COVID-19 infection in heart failure patients. Therefore, this study aimed to assess the plasma concentration of BNP, NT-proBNP, and ANP in a medium-sized cross-sectional case-control study involving 360 heart failure patients, both infected and uninfected with COVID-19. The heart failure patients were categorized into subgroups based on their Ejection Fraction (EF) percentage, namely heart failure with reduced EF (HFrEF), heart failure with mid-range EF (HFmrEF), and heart failure with preserved EF (HFpEF). Our findings demonstrate a significant increase in plasma levels of BNP and NT-proBNP in all heart failure patients, as well as in each subgroup (HFrEF, HFmrEF, and HFpEF) when infected with COVID-19, compared to uninfected heart failure patients. These established cardiac biomarkers have the potential to be utilized as future indicators for assessing the severity of COVID-19 infection in heart failure patients, thereby enhancing heart failure management and reducing irreversible cardiac damage.

Sacubitril/valsartan ameliorates renal tubulointerstitial injury through increasing renal plasma flow in a mouse model of type 2 diabetes with aldosterone excess.

Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified. Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2μg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO+VAL (valsartan), and ALDO+SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid. The ALDO+SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO+VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2, and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR. In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability.

Role of atrial natriuretic peptide in the dissociation between flow relations with ventricular mass and function in a community with volume-dependent hypertension.

Whether differential effects of volume load on left ventricular mass (LVM) and function occur in sustained volume-dependent primary hypertension, and the impact of atrial natriuretic peptide (ANP) on these effects, is unknown. From aortic pressure, velocity and diameter measurements and echocardiography, we determined in an African community (n = 772), the impact of systemic flow-induced increases in central pulse pressure (PPc) and circulating ANP (ELISA) on LVM and indexes of function. Stroke volume (SV), but not aortic flow (Q), was associated with LVM and mean wall thickness (MWT) beyond stroke work and confounders (p < 0.0001). Adjustments for SV markedly decreased the relationships between PPc and LVMI or MWT. However, neither SV, nor Q were independently associated with either myocardial s', e', or E/e' (p > 0.14) and adjustments for neither SV nor Q modified relationships between PPc and s', e' or E/e' (p < 0.005 to <0.0001). SV was nevertheless strongly and independently associated with ANP (p < 0.0001) and ANP was similarly strikingly associated with s' (p < 0.0001) and e' (p < 0.0005), but not E/e', independent of confounders and several determinants of afterload. Importantly, ANP concentrations were inversely rather than positively associated with LV diastolic dysfunction (DD) (p < 0.005) and lower rather than higher ANP concentrations contributed markedly to the ability to detect DD in those with, but not without LV hypertrophy. In populations with sustained volume-dependent hypertension, flow (SV)-related increases in PP have a major impact on LV structure, but not on function, an effect attributed to parallel striking beneficial actions of ANP on myocardial function.

Safety and feasibility of left atrial appendage inversion in swine: A proof-of-concept study for potential therapy to prevent embolic stroke.

Objective: Left atrial appendage (LAA) occlusion or exclusion has been used in patients with atrial fibrillation to prevent stroke, but the techniques and devices have shortcomings. This study aims to validate the safety and feasibility of a novel LAA inversion procedure. Methods: LAA inversion procedures were done in six pigs. Before the procedure and at 8 weeks postoperatively, heart rate, blood pressure, and electrocardiogram (ECG) were recorded. The serum concentration of atrial natriuretic peptide (ANP) was measured. The LAA was observed and measured by transesophageal echocardiogram (TEE) and intracardiac echocardiogram (ICE). At 8 weeks after LAA inversion, the animal was euthanized. The heart was collected for morphology and histology, including hematoxylin-eosin, Masson trichrome, and immunofluorescence staining. Results: TEE and ICE showed that LAA was inverted, and the inversion was maintained during the 8-week study duration. Food intake, body weight gain, heart rate, blood pressure, ECG, and serum ANP level were comparable before and after the procedure. Morphology and histological staining showed that there was no obvious inflammation or thrombus. Tissue remodeling and fibrosis were observed at the LAA inverted site. Conclusion: The inversion of LAA effectively eliminates the dead space of LAA and thus may reduce the risk of embolic stroke. The novel procedure is safe and feasible, but the efficacy in reducing embolization remains to be demonstrated in future studies.

Diagnostic value of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and their correlation with lipoproteins in dogs with myxomatous mitral valve disease

BackgroundMyxomatous mitral valve disease (MMVD) is the most common diagnosed cardiovascular disease in dogs. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) tests are used to diagnose congestive heart failure, but there are conflicting reports about their value in diagnosing the subclinical stages of MMVD in dogs. Moreover, the diagnostic value of blood lipoproteins in dogs with MMVD is still unclear. The purpose of this study was to assess the serum concentrations of ANP, BNP and lipoproteins of dogs with MMVD and to evaluate the correlation of the levels of ANP and BNP with lipoproteins.ResultsThis study was performed on 24 dogs with MMVD and 10 healthy dogs. Dogs with MMVD were classified in to stages B1 (n = 11), B2 (n = 6), C (n = 4) and D (n = 3) groups according to the classification suggested by American College of Veterinary Internal Medicine guidelines. Our results showed that the mean serum BNP levels were significantly increased for all MMVD groups compared to control dogs. The mean serum ANP levels for the stage B2, C and D groups were significantly higher than the control group, while the mean serum ANP concentrations did not differ significantly between the stage B1 and control groups. An increase in BNP level was observed in 87.5% of patients. Although BNP concentrations were elevated in 100% of dogs with stages C, D and B2, high BNP was observed in 72.72% of dogs with stage B1. Regarding ANP, 58.33% of patients had an increase in ANP. However, elevated ANP levels were found in only 27.27% of patients in stage B1, while increased ANP levels were observed in 66.66 and 100% of patients in stage B2 and C/D groups respectively. Also, in all patients with MMVD, the mean serum concentrations of high-density lipoprotein cholesterol (HDL-C) were approximately 1.7 to 2 times significantly lower than the control group. Additionally, the mean serum low-density lipoprotein cholesterol (LDL-C) increased significantly (1.9-2.7 times) compared to the control group.There was a significant inverse correlation between HDL-C and BNP, and HDL-C and ANP. LDL-C showed a significant positive correlation with BNP, and ANP. Also, LDL-C, but not HDL-C, had a significant positive correlation with LA/AO ratio, LVIDd, LVIDdN and VHS. BNP and ANP showed a significant positive correlation with LA/AO, LVIDd, LVIDdN and VHS.ConclusionsSerum BNP has a greater diagnostic value than serum ANP in dogs with MMVD. In addition, serum BNP can be used to determine the subclinical stages of B1 and B2 MMVD. This study also suggests that dogs with subclinical MMVD, showed an increase in BNP along with a decrease in HDL-C and an increase in LDL-C, which are known to be risk factors for cardiovascular diseases in human. However, it seems that high LDL-C is more involved in the pathogenesis of MMVD than low HDL-C. Therefore, periodic testing of serum lipoproteins is recommended in high-risk patients, even if total cholesterol levels are normal.

Attenuated Relationships Between Indexes of Volume Overload and Atrial Natriuretic Peptide in Uncontrolled, Sustained Volume-Dependent Primary Hypertension.

Whether systolic blood pressure (SBP) control in sustained volume-dependent primary hypertension is associated with blunted ANP (atrial natriuretic peptide) relationships with indexes of volume load is unknown. Systemic hemodynamics (central pressure, echocardiographic aortic velocity and diameter measurements in the outflow tract), circulating ANP concentrations (ELISA assays) and glomerular and tubular function (24-hour urine collections [n=519]) were determined in a community of African ancestry (n=772). As compared with those with a controlled SBP, those with an uncontrolled SBP (n=198) showed lower ANP concentrations (P<0.005) despite higher stroke volume and cardiac output (P<0.0001) and renal differences consistent with enhanced fluid retention. In those with a controlled SBP, fractional Na+ excretion (FeNa+; P<0.0005) and creatinine clearance (glomerular filtration rate; P<0.005) were inversely associated with ANP concentrations independent of confounders. Moreover, in those with a controlled SBP, stroke volume and cardiac output (P<0.0001) were independently and positively associated with ANP concentrations. In addition, in those with a controlled SBP, ANP concentrations were independently and inversely associated with systemic vascular resistance (SVR; P<0.0001) and aortic characteristic impedance (Zc; P<0.005). By contrast, in those with uncontrolled SBP, no relationships between either stroke volume (P>0.25), cardiac output (P>0.29), FeNa+ (P>0.77), or glomerular filtration rate (P>0.47) and ANP concentrations were noted. Furthermore, in those with an uncontrolled SBP, no relationships between ANP concentrations and SVR or Zc were observed (P>0.34). In a population where primary hypertension is strongly volume-dependent, those with an uncontrolled SBP have an attenuated relationship between ANP and both renal and hemodynamic indexes of volume overload and the vascular effects of ANP.

Cardiotoxicity of PFOA, PFOS, and PFOSA in Early Life Stage Zebrafish: Molecular Changes to Behavioral-level Response

The widespread use of perfluoroalkyl and polyfluoroalkyl substances (PFASs) globally has led to increased pollution in the environment and has subsequently posed health risks. Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorooctanesulfonamide (PFOSA) has been reported to induce immunotoxicity, endocrine toxicity, and developmental toxicity. However, the associated mechanisms and induction of cardiotoxicity following PFASs exposure remains poorly understood. Here, we explored the cardiac toxicity and associated mechanism in zebrafish embryos after exposure to PFOA, PFOS, and PFOSA at 1 and 10 μg/L by RNA sequencing, morphological and physiological assessment, and behavioral alterations. Ingenuity Pathway Analysis (IPA) was used to predict disease and functions following exposure and predicted that the cardiac system was significantly affected by these three PFASs. The upregulation of miR-16–5p was predicted to act as an upstream regulator and involved in PFAS-induced pericardial edema. Cardiac output, an abnormal cardiac morphology, and atrial natriuretic peptide content were significantly altered following PFASs exposure. Furthermore, behavioral-level alterations were seen following exposure to PFASs. Our results indicated that PFASs could induce cardiotoxicity in zebrafish during early life stage development, the toxicity of PFOA and PFOSA may induce a more severe response relative to PFOS at relatively high concentrations according to the PCA analysis of all the tested data.

Neuroendocrine hormone status and diuretic response to atrial natriuretic peptide in patients with acute heart failure.

Given the various effects of sacubitril/valsartan in heart failure, a deeper understanding of atrial natriuretic peptide (ANP) actions is warranted. Natriuresis is a fundamental action of ANP in acute heart failure (AHF), whereas the diuretic effect of ANP is different in each patient according to the diversity of renal response to ANP, which is affected by baseline plasma ANP status and deficiency of circulating ANP. Meanwhile, associations between other neuroendocrine hormones and the diuretic response to ANP are unclear. This study investigated the impact of pivotal neuroendocrine hormones on the diuretic effects of exogenous ANP, carperitide. Plasma ANP, renin, aldosterone, and vasopressin levels and the diuretic effect of 0.0125μg/kg/min of carperitide alone for the first 6h were prospectively evaluated in 75 patients with AHF. Lower ANP levels were significantly associated with a greater diuretic response to exogenous ANP (r=-0.35, P=0.002). Additionally, higher vasopressin levels were significantly related to the poor diuretic effects of exogenous ANP (r=-0.54, P<0.001). Plasma ANP and vasopressin concentrations were not significantly correlated (r=0.19, P=0.10). Baseline systolic blood pressure, renal function, and prior use of loop diuretics did not predict the diuretic response to exogenous ANP, whereas vasopressin levels independently predicted a diuretic response to exogenous ANP (P<0.001), as well as lower plasma ANP levels (P=0.027). Vasopressin status was significantly associated with the diuretic response to exogenous ANP in AHF, independent of plasma ANP status. The results may provide a better understanding of the actions of sacubitril/valsartan.

Fast versus slow infusion of 20% albumin: a randomized controlled cross-over trial in volunteers

BackgroundWe investigated whether plasma volume (PV) expansion of 20% albumin is larger when the fluid is administered rapidly compared with a slow infusion.MethodsIn this open-labeled randomized interventional controlled trial, 12 volunteers (mean age, 28 years) received 3 mL/kg of 20% albumin (approximately 225 mL) over 30 min (fast) and 120 min (slow) in a cross-over fashion. Blood hemoglobin and plasma albumin were measured on 15 occasions during 6 h to estimate the PV expansion and the capillary leakage of albumin and fluid.ResultsThe largest PV expansion was 16.1% ± 6.5% (mean ± SD) for fast infusion and 12.8% ± 4.0% for slow infusion (p = 0.52). The median area under the curve for the PV expansion was 69% larger for the fast infusion during the first 2 h (p = 0.034), but was then similar for both infusions. The half-life of the PV expansion did not differ significantly (median, 5.6 h versus 5.4 h, p = 0.345), whereas the intravascular half-life of the excess albumin was 8.0 h for fast infusion and 6.3 h for slow infusion (p = 0.028). The measured urine output was almost three times larger than the infused volume. The plasma concentration of atrial natriuretic peptide (MR-proANP) accelerated the capillary leakage of albumin and the urine flow.ConclusionsThe intravascular persistence of albumin was longer, but the fluid kinetics was the same, when 20% albumin was infused over 30 min compared with 120 min. We found no disadvantages of administering the albumin at the higher rate.Trial registration EU Clinical Trials Register, EudraCT2017-003687-12, registered September 22, 2017, https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-003687-12/SE

Diet-induced hypertension in rats is associated with increased renal vasoconstrictor response to angiotensin II after imitated endothelial dysfunction.

The mechanisms behind development of diet-induced hypertension remain unclear. The kidneys play a paramount role in blood volume and blood pressure regulation. Increases in renal vascular resistance lead to increased mean arterial blood pressure (MAP) due to reduced glomerular filtration rate and Na+ excretion. Renal vascular resistance may be increased by several factors, e.g. sympathetic output, increased activity in the renin-angiotensin system or endothelial dysfunction. We examined if a 14-week diet rich in fat, fructose or both led to increased renal vascular resistance and blood pressure. Sixty male Sprague-Dawley rats received normal chow (Control), high-fat chow (High Fat), high-fructose in drinking water (High Fructose), or a combination of high-fat and high-fructose diet (High Fat + Fruc) for 14weeks from age 4-weeks. Measurements included body weight (BW), telemetry blood pressures, renal blood flow in anesthetized rats, plasma concentrations of atrial natriuretic peptide and glucose, as well as vessel myography in renal segmental arteries. Body weight increased in both groups receiving high fat, whereas MAP increased only in the High Fat + Fruc group. Renal blood flow did not differ between groups showing that renal vascular resistance was not increased by the diets. After inhibiting nitric oxide and prostacyclin production, renal blood flow reductions to Angiotensin II infusions were exaggerated in the groups receiving high fructose. MAP correlated positively with heart rate in all rats tested. Our data suggest that diet-induced hypertension is not caused by an increase in renal vascular resistance. The pathophysiological mechanisms may include altered signaling in the renin-angiotensin system and increases in central sympathetic output in combination with reduced baroreceptor sensitivity leading to increased renal vasoconstrictor responses.

PO-638-04 LOW ATRIAL NATRIURETIC PEPTIDE TO BRAIN NATRIURETIC PEPTIDE RATIO WAS ASSOCIATED WITH LEFT ATRIAL REMODELING AND HOSPITALIZATION DUE TO HEART FAILURE IN PATIENTS WITH ATRIAL FIBRILLATION ABLATION

Deficiency of atrial natriuretic peptide (ANP) is thought to contribute to hemodynamic deterioration in case with advanced atrial remodeling due to atrial fibrillation (AF). However, little is known about the association between plasma ANP level and severity of left atrial remodeling or prognosis of heart failure in patients with AF. The purpose of this study was to investigate the association between ANP and left atrial remodeling or prognosis of heart failure in patients with AF ablation. Three hundred and seventy-three consecutive patients who underwent initial ablation for persistent AF (age, 67 ± 10 years; and females, 97 [26%]) were retrospectively enrolled. Plasma ANP and brain natriuretic peptide (BNP) concentration were measured before the procedure and ANP/BNP ratio was calculated. Left atrial appendage emptying velocity (LAAEV), left atrial low voltage areas (LVAs), and left atrial volume index (LAVI) were used as clinical factors of left atrial remodeling. Median plasma ANP level was 116 (71-178) pg/ml, and median ANP/BNP ratio was 0.65 (0.46-1.00). Plasma ANP levels did not correlated with LAAEV or LVAs. There was significant correlations between ANP/BNP ratio and LAAEV, LVAs, or LAVI. During the 24 months follow-up, freedom from hospitalization due to heart failure was significantly lower in patients with a ANP/BNP ratio ≤ 0.65 than in those with a ANP/BNP ratio > 0.65 (94.3% versus 99.5%, P<0.01). The secretion of ANP relative to BNP decrease along with progression of left atrial remodeling in patients with AF ablation. Additionally, hospitalization due to heart failure frequently occurred in patients with low secretion of ANP relative to BNP.

Modulation of atrial natriuretic peptide receptors in ovarian folliculogenesis

Specific receptors for atrial natriuretic peptide (ANP) located in intra-ovarian tissues are suggested to be involved in ovarian functions such as oocyte maturation and follicle development. However, the characteristics and modulation of its receptor in relation to ovarian folliculogenesis are not well defined. This study examined the properties of ANP receptors in the ovary using quantitative receptor autoradiography. In the pig ovary, the highest binding sites for 125I-ANP(1-28) were localized in the granulosa cell layer of the follicles as well as cumulus oophorous. The binding sites for 125I-ANP(1-28) on theca layer of the ovarian follicles were mainly localized in the external layer, but none was observed in the internal layer. Specific binding of 125I-ANP(1-28) was not found clearly in atretic follicles. In the corpus luteum, the binding site was not observed. Analysis of the competitive inhibition of the binding of 125I-ANP(1-28) to the granulosa and theca externa layers in various preovulatory follicles by increasing concentrations of unlabeled ANP(1-28) was consistent with a single high affinity for 125I-ANP(1-28). The maximal binding capacities of 125I-ANP(1-28) in granulosa layer were significantly increased in proportion to the development of ovarian follicles. However, no significant difference of binding capacities of 125I-ANP(1-28) was observed in theca externa layer. The binding affinities of 125I-ANP(1-28) in granulosa and theca externa layers were not different from each other. Especially, the correlation between specific binding of 125I-ANP(1-28) and follicle diameter. A significant correlation was revealed between specific binding of 125I-ANP(1-28) and follicle diameter (R = 0.88, p &lt; 0.0001) in granulosa layer, however, less relationship was detected in theca externa layer (R = 0.50, p &lt; 0.0001). Therefore, these results indicate that the biological ANP receptors exist in granulosa and the theca externa layers of the pig ovary, and suggest that the ANP receptors in granulosa layer may be related to the regulatory function of the ovarian follicullogenesis including oocyte maturation.

Adipose Lipolysis Regulates Cardiac Glucose Uptake and Function in Mice under Cold Stress.

The heart primarily uses fatty acids as energy substrates. Adipose lipolysis is a major source of fatty acids, particularly under stress conditions. In this study, we showed that mice with selective inactivation of the lipolytic coactivator comparative gene identification-58 (CGI-58) in adipose tissue (FAT-KO mice), relative to their littermate controls, had lower circulating FA levels in the fed and fasted states due to impaired adipose lipolysis. They preferentially utilized carbohydrates as energy fuels and were more insulin sensitive and glucose tolerant. Under cold stress, FAT-KO versus control mice had >10-fold increases in glucose uptake in the hearts but no increases in other tissues examined. Plasma concentrations of atrial natriuretic peptide and cardiac mRNAs for atrial and brain-type natriuretic peptides, two sensitive markers of cardiac remodeling, were also elevated. After one week of cold exposure, FAT-KO mice showed reduced cardiac expression of several mitochondrial oxidative phosphorylation proteins. After one month of cold exposure, hearts of these animals showed depressed functions, reduced SERCA2 protein, and increased proteins for MHC-β, collagen I proteins, Glut1, Glut4 and phospho-AMPK. Thus, CGI-58-dependent adipose lipolysis critically regulates cardiac metabolism and function, especially during cold adaptation. The adipose-heart axis may be targeted for the management of cardiac dysfunction.

Inhibition of endogenous ouabain by atrial natriuretic peptide is a guanylyl cyclase independent effect.

Endogenous ouabain (EO) and atrial natriuretic peptide (ANP) are important in regulation of sodium and fluid balance. There is indirect evidence that ANP may be involved in the regulation of endogenous cardenolides. H295R are human adrenocortical cells known to release EO. Cells were treated with ANP at physiologic concentrations or vehicle (0.1% DMSO), with or without guanylyl cyclase inhibitor 1,2,4 oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). Cyclic guanosine monophosphate (cGMP), the intracellular second messenger of ANP, was measured by a chemiluminescent immunoassay and EO was measured by radioimmunoassay of C18 extracted samples. EO secretion is inhibited by ANP treatment, with the most prolonged inhibition (90 min vs ≤ 60 min) occurring at physiologic ANP concentrations (50 pg/mL). Inhibition of guanylyl cyclase with ODQ, also reduces EO secretion. The inhibitory effects on EO release in response to cotreatment with ANP and ODQ appeared to be additive. ANP inhibits basal EO secretion, and it is unlikely that this is mediated through ANP-A or ANP-B receptors (the most common natriuretic peptide receptors) or their cGMP second messenger; the underlying mechanisms involved are not revealed in the current studies. The role of ANP in the control of EO synthesis and secretion in vivo requires further investigation.

The protein tyrosine kinase inhibitor genistein suppresses hypoxia-induced atrial natriuretic peptide secretion mediated by the PI3K/Akt-HIF-1α pathway in isolated beating rat atria.

Genistein, an isoflavonoid that can inhibit protein tyrosine kinase (PTK) phosphorylation, has been shown to play pivotal roles in the signal transduction pathways of hypoxic disorders. In this study, we established a rat model of isolated beating atrium and investigated the regulator role of genistein and its downstream signaling pathways in acute hypoxia-induced atrial natriuretic peptide (ANP) secretion. Radioimmunoassay was used to detect the ANP content in the atrial perfusates. Western blot analysis was used to determine the protein level of hypoxia-inducible factor 1α (HIF-1α), and GATA4 in the atrial tissue. The results showed that acute hypoxia substantially promoted ANP secretion, whereas this effect was partly attenuated by the PTKs inhibitor genistein (3 μM). By Western blotting analysis, we found that hypoxia-induced increase in phosphorylation of Akt and transcriptional factors, including HIF-1α, were also reversed by genistein. The perfused HIF-1α inhibitors rotenone (0.5μM) or CAY10585 (10μM) plus genistein significantly abolished the enhanced ANP section induced by hypoxia. Additionally, the perfused PI3K/Akt agonist insulin-like growth factor 1 (30μM) also abolished ANP secretion induced by genistein and inhibited expression of HIF-1α. In summary, our data suggested that acute hypoxia markedly increased ANP secretion by PTKs through the phosphoinositide-3 kinase (PI3K)/HIF-1α dependent pathway.

Hemodynamic phenotyping of transgenic rats with ubiquitous expression of an angiotensin-(1-7)-producing fusion protein.

Activation of the angiotensin (Ang)-converting enzyme (ACE) 2/Ang-(1-7)/MAS receptor pathway of the renin-angiotensin system (RAS) induces protective mechanisms in different diseases. Herein, we describe the cardiovascular phenotype of a new transgenic rat line (TG7371) that expresses an Ang-(1-7)-producing fusion protein. The transgene-specific mRNA and the corresponding protein were shown to be present in all evaluated tissues of TG7371 with the highest expression in aorta and brain. Plasma Ang-(1-7) levels, measured by radioimmunoassay (RIA) were similar to control Sprague-Dawley (SD) rats, however high Ang-(1-7) levels were found in the hypothalamus. TG7371 showed lower baseline mean arterial pressure (MAP), assessed in conscious or anesthetized rats by telemetry or short-term recordings, associated with increased plasma atrial natriuretic peptide (ANP) and higher urinary sodium concentration. Moreover, evaluation of regional blood flow and hemodynamic parameters with fluorescent microspheres showed a significant increase in blood flow in different tissues (kidneys, mesentery, muscle, spleen, brown fat, heart and skin), with a resulting decrease in total peripheral resistance (TPR). TG7371 rats, on the other hand, also presented increased cardiac and global sympathetic tone, increased plasma vasopressin (AVP) levels and decreased free water clearance. Altogether, our data show that expression of an Ang-(1-7)-producing fusion protein induced a hypotensive phenotype due to widespread vasodilation and consequent fall in peripheral resistance. This phenotype was associated with an increase in ANP together with an increase in AVP and sympathetic drive, which did not fully compensate the lower blood pressure (BP). Here we present the hemodynamic impact of long-term increase in tissue expression of an Ang-(1-7)-fusion protein and provide a new tool to investigate this peptide in different pathophysiological conditions.