Plasma Atrial Natriuretic Peptide Research Articles

Impact of epicardial ablation of concomitant atrial fibrillation on atrial natriuretic peptide levels and atrial function in 6 months follow-up: does preoperative ANP level predict outcome of ablation?

BackgroundEpicardial ablation concomitant to cardiac surgery is an easy and safe approach to treat atrial fibrillation (AF), but its efficacy in longstanding persistent (LsPe) AF remains intermediate. Although larger left atrial size has been associated with worse outcome after ablation, biochemical predictors of success are not well established. The aim of this study was to evaluate relationship between biochemical marker, echo-characteristic and cardiac rhythm in 6 months follow-up after epicardial ultrasound (HIFU) ablation.MethodsWe included 78 consecutive patients, who underwent elective cardiac surgery. 42 patients with AF (11.9% paroxysmal, 23.8% persistent, 64.3% LsPeAF) underwent concomitant HIFU ablation (AF ablation group), 16 with AF underwent cardiac surgery without ablation (AF control) and 20 had preoperatively normal sinus rhythm (SR control). We measured plasma ANP secretion before, on postoperative day (POD) 1, POD 7 as well as 3 and 6 months after surgery. Moreover, we estimated cardiac rhythm and atrial mechanical function by Atrial Filling Fraction (AFF) and A-wave velocity in follow-up.ResultsBaseline ANP levels were higher in patients with LsPeAF, as compared to the paroxysmal and permanent AF and to the SR control group. Patients with LsPeAF (n = 27) who converted to SR had preoperatively smaller left atrial diameter (LAD) and LA area (p < 0.05) and higher ANP level (p = 0.009) than those who remained in AF at 6 months after ablation. Multivariate regression analysis revealed that only preoperative ANP level was an independent predictor of cardiac rhythm after ablation. Patients with LsPeAF and preoperative ANP >7.5 nmol/l presented with SR in 80%, in contrast to those with ANP <7.5 nmol/l who converted to SR in 20%. We detected gradual increase of AFF and A-velocity at 6 months after ablation (p < 0.05) solely in AF ablation group. ANP levels were increased on POD 1 in ablation group (p < 0.05), without changes in further follow-up.ConclusionOur results indicate that preoperative ANP levels may be a new biochemical predictor of successful epicardial ablation in patients with concomitant LsPeAF. HIFU ablation caused a significant improvement of atrial mechanical function and gradual increase of AFF and did not associate with alteration of atrial endocrine secretion at 6 months follow-up.

Atrial natriuretic peptide as a predictor of atrial fibrillation in a male population study. The Study of Men Born in 1913 and 1923

BackgroundAtrial fibrillation is one of the most common arrhythmias in clinical practice and it is often diagnosed after a complication occurs. The study aimed to evaluate the predictive value of atrial natriuretic peptide (ANP) for atrial fibrillation in a male population-based study. Methods and resultsThis study is a part of the “Study of Men Born in 1913 and 1923”, a longitudinal prospective cohort study of men, living in the city of Gothenburg in Sweden. A population-based sample of 528 men was investigated in 1988 when they were aged 65years (n=134) and 75years (n=394), and they were followed up for 16years. Blood samples were collected from all 528 men at baseline and plasma ANP levels were analyzed by radioimmunoassay. Hazard ratios were estimated by competing-risk regression analysis.One hundred five participants were excluded because of a prior diagnosis of atrial fibrillation, congestive heart failure, severe hypertension, or severe chronic renal insufficiency. Of the remaining 423 participants, 90 men were diagnosed with atrial fibrillation over the 16-year follow-up. In multivariable analysis, men in the two highest quartiles of ANP levels had a significantly higher risk for atrial fibrillation compared with men in the lowest ANP quartile. The adjusted ratio was 3.14 (95% CI 1.59–6.20) for the third ANP quartile and 3.36 (95% CI 1.72–6.54) for the highest quartile of ANP level. ConclusionsIn this population-based longitudinal study, we found that elevated ANP levels at baseline predicted atrial fibrillation during a follow-up time of 16years.

Postprandial effects of a high salt meal on serum sodium, arterial stiffness, markers of nitric oxide production and markers of endothelial function

AimThe aim of the study was to determine if a high salt meal containing 65 mmol Na causes a rise in sodium concentrations and a reduction in plasma nitrate/nitrite concentrations (an index of nitric oxide production). Secondary aims were to determine the effects of a high salt meal on augmentation index (AIx) a measure of arterial stiffness and markers of endothelial function. Methods and resultsIn a randomised cross-over study 16 healthy normotensive adults consumed a low sodium soup containing 5 mmol Na and a high sodium soup containing 65 mmol Na. Sodium, plasma nitrate/nitrite, endothelin-1 (ET-1), C-reactive protein (CRP), vasopressin (AVP) and atrial natriuretic peptide (ANP) concentrations before and every 30 min after the soup for 2 h. Blood pressure (BP) and AI were also measured at these time points.There were significant increases in serum sodium, osmolality and chloride in response to the high sodium meal. However plasma nitrate/nitrite concentrations were not different between meals (meal p = 0.812; time p = 0.45; meal × time interaction p = 0.50). Plasma ANP, AVP and ET-1 were not different between meals. AI was significantly increased following the high sodium meal (p = 0.02) but there was no effect on BP. ConclusionsA meal containing 65 mmol Na increases serum sodium and arterial stiffness but does not alter postprandial nitrate/nitrite concentration in healthy normotensive individuals. Further research is needed to explore the mechanism by which salt affects vascular function in the postprandial period.This trial was registered with the Australian and New Zealand Clinical Trials Registry Unique Identifier: ACTRN12611000583943http://www.anzctr.org.au/trial_view.aspx?ID=343019.

The clinical value of atrial natriuretic peptide in early diagnosis of sepsis

To evaluate the clinical value and specificity of atrial natriuretic peptide (ANP) in early diagnosis of sepsis. A prospective study was performed. Data of patients with sepsis were consecutively collected from September 2007 to December 2012 according to the international criteria for the diagnosis of sepsis, and that of 114 patients admitted to intensive care unit (ICU) and the cadre health care ward were divided into three groups: systemic inflammatory response syndrome (SIRS) group (n=37), sepsis group (n=41) and severe sepsis group (including severe sepsis and septic shock, n=36). Venous blood of each patient was drawn instantly when admitted to ICU. The concentration of plasma ANP in each group was determined on the 1st day using a new type of sandwich immunofluorescence assay, and other biomarkers, such as procalcitonin (PCT, detected with double antibody immunochemi luminometry), blood lactic acid (detected with electrode meter), and C-reactive protein (CRP, detected with immunonephelometric analysis), and the acute physiology and chronic health evaluation II (APACHEII) score was recorded. APACHEII score and biomarkers were compared among three groups. The risk factor for severity was confirmed with stepwise regression, and the value of each index in early diagnosis of sepsis was analyzed with receiver operating characteristic (ROC) curve. The plasma concentration of ANP exhibited a gradual increase with the aggravation of the disease, and the median ANP value was found to be highest in the severe sepsis group compared with SIRS group and sepsis group [μg/L: 0.26 (0.22) vs. 0.19 (0.05), 0.21 (0.08), P<0.01 and P<0.05]. The regression equation was established at y=0.69 + 0.66APACHEIIscore + 1.285 ANP value, with group as independent variable, and APACHEII score, ANP, PCT, CRP and blood lactic acid value as dependent variables. It could be concluded that APACHEII score and ANP value were correlated with severity of sepsis, and accordingly they were regarded as the independent predictors of severity of sepsis. It was found through the ROC curve analysis of ANP in the sepsis patients, that the area under the ROC curve for ANP [0.805, P=0.000, 95% confidence interval (95%CI) 0.726-0.883, sensitivity 75.8%, specificity 78.4%] was similar with the area under the APACHEII score (0.820, P=0.000, 95%CI 0.742-0.897, sensitivity 68.4%, specificity 78.4%), and it was apparently higher than AUCs of PCT (0.716, P=0.000, 95%CI 0.622-0.810, sensitivity 67.1%, specificity 62.2%), CRP (0.569, P=0.236, 95%CI 0.463-0.675, sensitivity 76.3%, specificity 41.5%), or blood lactic acid (0.566, P=0.254, 95%CI 0.453-0.679, sensitivity 75.0%, specificity 48.6%). Plasma ANP concentration is clinically valuable in early diagnosis and severity assessment of sepsis, and it is more specific and sensitive than biomarkers PCT and CRP.

Stimulation of ANP by angiotensin-(1-9) via the angiotensin type 2 receptor

AimsAngiotensin-(1-9) [Ang-(1-9)] and Ang-(1-7) are cleaved by Ang converting enzyme 2 forming Ang I and Ang II, respectively, and the truncated Angs play a role in regulating atrial natriuretic peptide (ANP) secretion. Previously, we found that Ang-(1-7) stimulates ANP secretion via the Mas receptor. However, the effect of Ang-(1-9) on ANP secretion is still unknown. The aim of the present study is to determine whether Ang-(1-9) stimulates ANP secretion and to characterize the signaling pathway involved in stimulating secretion. Main methodsWe examined the effects of Ang-(1-9) on ANP secretion and atrial contractility with and without inhibitors in isolated perfused atria. Key findingsAng-(1-9) stimulated ANP secretion and concentration without change in atrial contractility. Ang-(1-9)-induced-ANP secretion was increased from 5% to 60% by 3μM Ang-(1-9) during the low-stretch state of the atrium. This stimulatory effect of Ang-(1-9) on ANP secretion was attenuated by pretreatment with an Ang II type 2 receptor (AT2R) antagonist but not by AT1R or Mas receptor antagonist. In addition, pretreatment with inhibitors of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) blocked Ang-(1-9)-induced ANP secretion. In the high-stretch atrial state, Ang-(1-9)-induced ANP secretion was increased more than in the low-stretch state following addition of 1μM Ang-(1-9) (from 108% to 170%). In an in vivo experiment, acute infusion of Ang-(1-9) increased plasma ANP level without altering arterial blood pressure. This effect was attenuated by pretreatment with AT2R antagonist but not by Mas receptor antagonist. SignificanceThese results suggest that Ang-(1-9) stimulates ANP secretion via the AT2R-PI3K-Akt-NO-cGMP pathway.

The Impact of Atrial Natriuretic Peptide on Anxiety, Stress and Craving in Patients with Alcohol Dependence

Atrial natriuretic peptide (ANP) is well known to modulate fluid and electrolyte homeostasis but also to counter-regulate hypothalamic-pituitary-adrenal (HPA) axis activity. Correspondingly, recent studies suggest an important role of ANP in the neurobiology of anxiety. Preclinical and clinical data now provide evidence for an involvement of ANP in the pathophysiology of addictive behavior. The present study aims to elucidate the effects of ANP on alcohol-dependent patients' anxiety, perceived stress and craving during alcohol withdrawal. A sample of 59 alcohol-dependent inpatients was included in the analysis. A blood sample was taken at day 14 of detoxification in order to assess the concentrations of ANP and cortisol in plasma. In parallel, we assessed patients' alcohol craving, using the Obsessive Compulsive Drinking Scale, as well as anxiety (State-Trait Anxiety Inventory). Patients' stress levels were assessed using the Perceived Stress Scale. We found a significant negative association between patients' ANP plasma concentrations and anxiety, craving for alcohol and perceived stress. Regression analyses suggest that ANP is a significant predictor both for patients' perceived stress and for the severity of anxiety during early abstinence. The association of patients' ANP plasma levels and craving is suggested to be mediated by perceived stress. Our results suggest that the association of patients' ANP plasma levels and craving is mediated by their perceived stress. For this reason, intranasal application of ANP may prove to be a new avenue for the treatment of alcohol dependence in patients exhibiting high levels of perceived stress.

The role of estradiol in adrenal insufficiency and its interaction with corticosterone on hydromineral balance

Estradiol (E2) plays an important role in controlling the homeostasis of body fluids. Several studies have reported the involvement of the hypothalamic pituitary adrenal axis (HPA) in the homeostatic control of hydromineral balance and the influence of estrogens on the modulation of this system. Nevertheless, until now, the physiological relevance of HPA axis activity on the hydromineral balance in females has not yet been fully elucidated. Therefore, the objective of the present study was to evaluate the effects of E2 (20μg/animal) pretreatment on neuroendocrine and hydroelectrolyte changes induced by adrenalectomy (ADX) with or without glucocorticoid hormone replacement (corticosterone, CORT; 10mg/kg) in ovariectomized rats (OVX). The results show that sodium appetite, natriuresis and the elevated plasma angiotensin II (ANG II) concentration induced by ADX were attenuated by E2 pretreatment. Additionally, a reduction of AT1 mRNA expression in the subfornical organ (SFO) and an increase in plasma atrial natriuretic peptide (ANP) concentrations by E2 pretreatment were observed. E2 pretreatment reversed the reduction in water intake induced by ADX in ADX CORT-replaced rats. Moreover, E2 pretreatment attenuated corticotropin releasing factor (CRF) mRNA expression in the paraventricular nucleus (PVN) induced by ADX. In contrast, E2 pretreatment increased CRF mRNA expression in the PVN in ADX CORT-replaced rats. Taken together, these results suggest that E2 has an important role in the modulation of behavioral and neuroendocrine responses involved in the maintenance of body fluid homeostasis in ADX rats with or without glucocorticoid replacement therapy.

Fat Mass Localization Alters Fuel Oxidation during Exercise in Normal Weight Women

Abdominal and lower body fat mass tissues exhibit particular metabolic profiles at rest and during exercise. However, data are missing in normal weight women during exercise. The purpose of this study was to investigate the effect of low (LA/LB) and high (HA/LB) abdominal to lower body (A/LB) fat mass ratio on metabolic and hormonal responses during exercise in premenopausal normal weight women. After preliminary testing (V˙O2max and body composition assessment), substrate oxidation (RER, lipid, and carbohydrate oxidation rates), metabolic response (glycerol, free fatty acids, and glucose), and hormonal response (insulin, growth hormone, atrial natriuretic peptide, adrenaline, and noradrenaline) were determined during exercise (45 min at 65% of V˙O2max) in 21 premenopausal normal weight women (10 HA/LB women vs 11 LA/LB women). Waist circumference was significantly higher in HA/LB women compared with LA/LB women (P < 0.01). No difference in other anthropometric characteristics, V˙O2max, and resting blood values was observed between the two groups. LA/LB subjects exhibited greater lipid oxidation rates compared with HA/LB women during exercise (P < 0.01). This occurred with lower plasma insulin (P < 0.05) and glucose (P < 0.05) concentrations and higher plasma free fatty acids (P < 0.05), glycerol (P < 0.05), growth hormone (P < 0.05), and atrial natriuretic peptide levels (P < 0.01) during exercise in the LA/LB group compared with the HA/LB group. The present study demonstrated that LA/LB women exhibited an increase in whole-body lipid mobilization and use during exercise compared with HA/LB counterparts. This greater reliance on lipid as fuel metabolism during exercise could be explained by substrate availability and metabolic and hormonal responses. It appeared that LA/LB women exhibited greater metabolic flexibility during an exercise bout of 45 min at 65% of V˙O2max on cycle ergometer.

Increased catabolic activity in adipose tissue of patients with chronic heart failure

Patients with chronic heart failure (CHF) have an increased catabolic state that affects both muscle and adipose tissue (AT), and may ultimately result in cardiac cachexia. Increased plasma levels of ANP might contribute to increased lipid mobilization and oxidation in CHF. We tested the hypothesis that increased plasma ANP levels are associated with an increased catabolic (lipolytic) state of white AT in patients with CHF. After an overnight fast, AT metabolism was studied by microdialysis in patients with CHF and healthy controls of a similar age and body composition (both n = 8). AT glycolytic and lipolytic activities were assessed at rest (fasting) and after an oral glucose load (oGL). Fasting and post-prandial profiles of serum glucose, insulin, and free fatty acids and of dialysate glucose did not differ significantly between patients and controls. In contrast, fasting dialysate lactate and glycerol levels were two-fold higher in patients vs. controls (lactate, 0.51 ± 0.10 and 0.26 ± 0.06 mmol/L, P < 0.01; glycerol, 116 ± 18 and 50 ± 8 µmol/L, P < 0.001), indicating increased AT glycolytic and lipolytic rates in patients. After an oGL, dialysate lactate increased ∼2- and 2.5-fold, whereas dialysate glycerol decreased by ∼60% and 50% in patients vs. controls, but metabolite levels were always significantly higher in patients vs. controls (all P < 0.05). Plasma ANP levels were increased in patients and significantly correlated with adipose tissue dialysate glycerol. In patients wiuth CHF, there is a direct correlation between plasma ANP levels and increased AT catabolic (lipolytic) state. This might contribute to AT wasting and the development of cardiac cachexia in patients with CHF.

Low Plasma Atrial Natriuretic Peptide: A New Piece in the Puzzle of Polycystic Ovary Syndrome

It is believed that a dysfunction in adipose tissue plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). Natriuretic peptides are hormones that regulate cardiovascular and body fluid homeostasis and adipose tissue metabolism. Natriuretic peptide levels are reduced in individuals with obesity and diabetes. This study aimed to investigate whether natriuretic peptide levels are altered in women with PCOS and whether they correlate with adiponectin levels or insulin sensitivity markers. This was a cross-sectional study at a referral center in a teaching hospital. We evaluated 40 patients diagnosed with PCOS according to the Rotterdam criteria and 36 control women matched for age and body mass index. We measured serum adiponectin, plasma atrial natriuretic peptide (ANP), and plasma brain natriuretic peptide using enzyme immunoassays in both groups. We evaluated metabolic markers, such as fasting glucose, insulin, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides. In addition, we calculated the homeostasis model assessment for insulin resistance index (HOMA-IR) and the lipid accumulation product (LAP) index and tested the linear correlations between these metabolic indices and the plasma ANP and serum adiponectin concentrations. ANP and adiponectin were reduced in the PCOS group compared with the control group (P = 0.010 and P = 0.014, respectively). The brain natriuretic peptide concentration did not differ between the two groups (P = 0.883). There was no correlation between ANP and any of the metabolic markers. In the control group, the serum adiponectin level was inversely correlated with BMI (P = 0.011), waist circumference (P = 0.021), insulin (P = 0.013), fasting glucose (P = 0.010), homeostasis model assessment for insulin resistance index (P = 0.007), and lipid accumulation product (P = 0.022). Remarkably, none of these correlations were observed in the women with PCOS. Women with PCOS had lower ANP and adiponectin compared with controls matched for age and BMI. Thus, the mechanisms that affect ANP and adiponectin production and clearance may be altered in PCOS, regardless of adiposity. These hormones may be involved in the metabolic features of PCOS.

Effects of acute and subchronic AT1 receptor blockade on cardiovascular, hydromineral and neuroendocrine responses in female rats

Female Wistar rats were ovariectomized (OVX) and separated into two groups that received either estradiol cypionate (EC, 40μg/kg, sc; OVX-EC) or vehicle (corn oil, sc; OVX-oil) for 14 consecutive days. On the 7th day of treatment, a subset of animals from both the OVX-oil and OVX-EC groups was subjected to subchronic losartan (AT1 receptor antagonist) treatment (0.1g/L in drinking water; ~15mg/kg/day) for 7days. Other group of OVX-oil and OVX-EC rats was submitted to an acute losartan injection (100mg/kg, ip) on the 14th day of hormone replacement. In both protocols, the following parameters were measured: I) mean arterial pressure (MAP) and heart rate (HR); II) water and 0.3M saline intake; III) angiotensin II (ANG II), atrial natriuretic peptide (ANP), vasopressin (AVP) and oxytocin (OT) plasma concentrations; and IV) urinary and plasma sodium concentrations. Acute AT1 blockade induced a significant reduction in the MAP in the OVX rats, resulting in increased HR and water intake, which were attenuated by estradiol therapy. Acute AT1 blockade also increased ANG II and OT and reduced ANP plasma concentrations, with no changes in AVP secretion. In addition, acute hypotension was accompanied by a decrease in natriuresis, which was unaltered by estradiol. Subchronic AT1 blockade induced a significant decrease in MAP without changing HR in both groups. Additionally, subchronic losartan treatment induced sodium appetite in OVX rats. Prolonged AT1 blockade increased ANG II and AVP and reduced ANP plasma concentrations. Moreover, it increased natriuresis but did not alter plasma OT concentrations. Finally, estradiol treatment attenuated the increase in salt intake and plasma ANG II concentrations induced by subchronic AT1 blockade. In conclusion, our results suggest differential adaptive responses to the acute or subchronic losartan treatment in OVX and OVX-EC rats.

Chronic uninephrectomy in a large animal is characterized by preservation of cardiovascular homeostasis but with cardiorenal activation of the cGMP system together with atrial fibrosis

Purpose: While renal donation is safe and widely employed for the treatment of endstage chronic kidney disease, recent experimental and human studies suggest complex cardiovascular adaptation that may impact long-term cardiovascular homeostasis. Indeed, in a large animal model of acute uninephrectomy (UNX) we observed reduced CO and increased SVR. Here we define chronic cardiovascular, renal and humoral adaptation in a large animal model 12 weeks after UNX with the goal of understanding integrative adaptations so as to advance possible cardiorenal protective strategies in the setting of mild renal insufficiency and UNX commonly associated with renal donation. Methods: Dogs were assigned to UNX (n=6) or sham operation (n=6). Echocardiography was performed at baseline and after 12 weeks. At 12 weeks cardiovascular, renal and humoral functions were assessed invasively. Fibrosis was assessed by Picrosirius red staining, and microarray analyses were performed on tissue from the left atrium (LA) and left ventricle (LV). Data are presented as mean±SD, * indicates p<0.05. Results: UNX dogs had compensatory increased left kidney (LK) weight at 12 weeks (80±10 vs. 59±5g, *) as well as increased LK GFR (59±11 vs. 41±6 mL/min, *). The groups were equal regarding MAP, PAP, PCWP, CO and SVR, and diastolic and systolic functions were unaltered in both groups 12 weeks after surgery. Plasma ANP, BNP and aldosterone were not different after 12 weeks, however plasma cGMP was higher in the UNX dogs (6.2±1.2 vs. 4.6±1.0 pmol/mL, *). LK urinary cGMP excretion was increased in the UNX dogs (1132±325 vs. 667±121 pmol/min, *) and there was a trend for increased renal generation of cGMP (UNX 777±345 vs. sham 475±112 pmol/min, p=0.07). Left atrial fibrosis was higher in the UNX group (13.7±5.1 vs. 7.7±2.3%, *). The UNX group had > 2 fold significant changes in the expression of 10 genes in the LA and 7 genes in the LV, associated with cardiac remodeling. Conclusion: UNX in a large animal is characterized by compensatory renal hypertrophy and preserved cardiovascular homeostasis after 12 weeks. Importantly however, the cardiorenal protective cGMP system is activated which may reflect triggering of endogenous vasodilating pathways mediating the preserved cardiovascular and renal function. Furthermore, our model is characterized by subclinical atrial fibrosis and altered remodeling-related gene expressions in the LA and LV. These studies provide insights into the complex responses to UNX and possible cGMP therapeutic strategies for cardioprotection in the setting of reduced renal mass.

Effect of hemodyalysis on precursor proBNP and glycosylated NT-proBNP in end-stage renal disease patients

Background: Brain natriuretic peptide (BNP) is established biomarker for cardiovascular diseases. Recent studies have shown that unprocessed precursor proBNP circulates in the healthy individuals, and its levels in plasma are increased in severe heart failure patients. However, since current BNP immunoassay crossreacts proBNP, it is important to consider the significance of proBNP on clinical situation of BNP elevation. In addition, recent study has shown that most proBNP is glycosylated, and that NT-proBNP is also glycosylated in human plasma, and current NT-proBNP assay underestimates the glycosylated NT-proBNP. Recent developed super-flux dialyzer can remove middle-sized molecular solutes such as β2-microgloburin. In this study, we investigated the effects of hemodialysis using super-flux dialyzer on the glycosylated proBNP, glycosylated NT-proBNP, and BNP-related other peptide in patients with end-stage renal disease (ESRD). Method: Thirty-six ESRD patients with hemodialysis were studied. We measured plasma BNP (which was defined as BNP messured with current BNP assay system), proBNP, and mature BNP (which was defined as total BNP- proBNP), by our newly developed immunoassay before and after hemodialysis. Plasma glycosylated NT-proBNP and nonglycosylated NT-proBNP was measured by Elecsys II after deglycosylating enzyme treatment such as neuramoinidase and O-glycosydase. We also measured plasma ANP and cGMP by radioimmunoassay. Results: After hemodialysis, BNP (-28%), proBNP (-20%), mature BNP (-47%), glycosylated NT-proBNP (-33%), nonglycosylated NT-proBNP (-45%), ANP (-52%), and cGMP (-63%) significantly decreased. The decreasing ratio did not correlated with any indices of reduction of plasma volume; however, these peptides decreased after hemodialysis in a molecular weight dependent manner. ProBNP/total BNP ratio and glycosylated NT-proBNP/nonglycosylated NT-proBNP ratio increased after hemodialysis. ProBNP/total BNP ratio positively correlated with hemodialysis vintage and negatively correlated with left atrial dimater and systolic blood pressure, whereas glycosylated NT-proBNP/nonglycosylated positively correlated with parathyroid hormone levels. Conclusion: These results suggest that hemodialysis modulates profile of BNP and its related peptide, and it may be important to consider the effect of this modulation on the pathological conditions in ESRD patients in super-flux dialyzer era.

What have genome-wide association studies taught us about cGMP and blood pressure regulation?

Background Hypertension (HTN) is a major worldwide cause of stroke, heart failure, myocardial infarction, and chronic kidney disease. Mechanisms of blood pressure regulation have previously been elucidated from the study of animal models, Mendelian hyper- and hypo-tension in humans, and drug treatment trials. More recently, genome-wide association studies (GWASs) have offered unbiased approaches to identify novel mechanisms contributing to blood pressure control. We and others have reported candidate gene and GWASs that have identified common genetic variants of modest effect on blood pressure that fall in pathways involving natriuretic peptide and nitric oxide signalling [1-3]. Results Common variant rs5068 in the 3’ UTR of NPPA ,w hich encodes the atrial natriuretic peptide (ANP), is associated with higher plasma ANP and lower blood pressure and odds of hypertension [2]. We have now completed a genotype-directed physiologic study of 8 heterozygotes and 23 major homozygotes demonstrating that the variant alters the “set point” of ANP (p=0.02) but does not alter the ANP response to high vs low sodium diet (p<0.0001) or to intravenous saline infusion (p<0.0001, in press); additional evidence for the mechanism by which this variant acts will be presented in a separate abstract. Downstream of the natriuretic peptide system, a common noncoding variant at a locus including NPR3, encoding the natriuretic peptide clearance receptor, has been associated with blood pressure although it is not associated with plasma ANP or BNP [3]. A common variant at the locus including ENOS, encoding endothelial nitric oxide synthase, is associated with blood pressure and hypertension [4,5]. Lastly, an intronic variant in GUCY1A3, encoding the alpha subunit of soluble guanylate cyclase, is associated with blood pressure and myocardial infarction risk. Conclusion The natriuretic peptide and nitric oxide systems are important contributors to blood pressure regulation in humans and represent strong targets for pharmacologic intervention to reduce the burden of disease from hypertension.

The effects of super-flux (high performance) dialyzer on the plasma glycosylated pro-B-type natriuretic peptide (proBNP) and glycosylated N-terminal proBNP in end-stage renal disease patients on dialysis

Background: Plasma BNP levels are predictive of prognosis in hemodialysis patients. However, recent studies showed that the current BNP immunoassay cross-reacts with glycosylated proBNP, and the NT-proBNP assay underestimates glycosylated NT-proBNP. In addition, the recently developed high performance dialyzer removes medium-sized molecular solutes such as b2-microgloburin. We therefore investigated the effects of high performance dialysis on measured levels of glycosylated proBNP, glycosylated NT-proBNP and other BNP-related peptides in end-stage renal disease (ESRD) patients on hemodialysis. Method: The relationships between clinical parameters and BNP-related molecule were also investigated. We used our newly developed immunoassay to measure plasma total BNP and proBNP in 105 normal subjects and 36 ESRD patients before and after hemodialysis. Plasma NT-proBNP was measured using Elecsys II after treatment with or without deglycosylating enzymes. We also measured plasma ANP and cGMP using radioimmunoassays. Results: All the measured BNP-related peptides were significantly higher in ESRD patients than healthy subjects. Total BNP (238.9%), proBNP (229.7%), glycoNT-proBNP (245.5%), nonglycoNT-proBNP (253.4%), ANP (250.4%) and cGMP (272.1%) were all significantly reduced after hemodialysis, and the magnitude of the reduction appeared molecular weightdependent. Both the proBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios were increased after hemodialysis. The former correlated positively with hemodialysis vintage and negatively with systolic blood pressure, while the latter correlated positively with parathyroid hormone levels. Conclusion: These results suggest that hemodialysis using super-flux dialyzer removes BNP-related peptides in a nearly molecular weight-dependent manner. The ProBNP/total BNP and glycoNT-proBNP/nonglycoNT-proBNP ratios appear to be influenced by hemodialysis-related parameters in ESRD patients on hemodialysis.

Assessment of the left atrial volume index and plasma NT-proANP level in patients with acute ST-elevation myocardial infarction

OBJECTIVES:Acute ST-elevation myocardial infarction is associated with ventricular dysfunction due to ischemia-induced progressive myocardial damage. The decrease in ventricular compliance causes left atrial dilatation and stretching of the atrial myocardium, which are the main stimuli for the secretion of atrial natriuretic peptide. The aim of this study was to evaluate left atrial dimensions and atrial natriuretic peptide levels in patients early after their first acute ST-elevation myocardial infarction and assess the probable interaction between coronary lesions and these measurements.METHODS:A total of 110 patients with acute myocardial infarction and 50 controls were studied. Plasma atrial natriuretic peptide was measured at admission. Left ventricular function, diameter, and volume index were evaluated using transthoracic echocardiography. Gensini and vessel scores of the patients who underwent coronary angiography were calculated.RESULTS:Plasma atrial natriuretic peptide in the patients with myocardial infarction was increased compared with that in controls (3.90±3.75 vs. 1.35±0.72 nmol/L, p<0.001). Although the left atrial diameter was comparable in patients and controls, the left atrial volume index was increased in patients with acute myocardial infarction (26.5±7.1 vs. 21.3±4.9 mL/m2, p<0.01). Multivariate regression analysis showed a strong independent correlation between the left atrial volume index and the plasma atrial natriuretic peptide level (β = 0.23, p = 0.03).CONCLUSIONS:The left atrial volume index and plasma atrial natriuretic peptide level were correlated in patients with acute myocardial infarction.

Angiotensin AT2 receptor agonist stimulates high stretch induced- ANP secretion via PI3K/NO/sGC/PKG/pathway

Angiotensin II (Ang II) type 1 receptor (AT1R) mediates the major cardiovascular effects of Ang II. However, the effects mediated via AT2R are still controversial. The aim of the present study is to define the effect of AT2R agonist CGP42112A (CGP) on high stretch-induced ANP secretion and its mechanism using in vitro and in vivo experiments. CGP (0.01, 0.1 and 1μM) stimulated high stretch-induced ANP secretion and concentration from isolated perfused rat atria. However, atrial contractility and the translocation of extracellular fluid did not change. The augmented effect of CGP (0.1μM) on high stretch-induced ANP secretion was attenuated by the pretreatment with AT2R antagonist or inhibitor for phosphoinositol 3-kinase (PI3K), nitric oxide (NO), soluble guanylyl cyclase (sGC), or protein kinase G (PKG). However, antagonist for AT1R or Mas receptor did not influence CGP-induced ANP secretion. In vivo study, acute infusion of CGP for 10min increased plasma ANP level without blood pressure change. In renal hypertensive rat atria, AT2R mRNA and protein levels were up-regulated and the response of plasma ANP level to CGP infusion in renal hypertensive rats augmented. The pretreatment with AT2R antagonist for 10min followed by CGP infusion attenuated an increased plasma ANP level induced by CGP. However, pretreatment with AT1R or Mas receptor antagonist unaffected CGP-induced increase in plasma ANP level. Therefore, we suggest that AT2R agonist CGP stimulates high stretch-induced ANP secretion through PI3K/NO/sGC/PKG pathway and these effects are augmented in renal hypertensive rats.

臨床 本態性高血圧症における血漿ANP,BNP濃度測定の意義

臨床 本態性高血圧症における血漿ANP,BNP濃度測定の意義

Atrial natriuretic peptide and cardiac troponin I concentrations in healthy Warmblood horses and in Warmblood horses with mitral regurgitation at rest and after exercise

ObjectiveAtrial natriuretic peptide (ANP) and cardiac troponin I (cTnI) serve as biomarkers for increased cardiac pressure/volume loading and for myocardial stress or damage. The objective was to describe the time course of plasma ANP concentrations (CpANP) and plasma cTnI concentrations (CpcTnI) in horses with mitral regurgitation (MR) compared to healthy horses at rest and after exercise, and to describe the relationship of CpANP with cardiac dimensions and intracardiac pressures. Animals15 healthy Warmblood horses and 7 Warmblood horses with MR. MethodsCardiac dimensions at rest were measured using echocardiography. All horses underwent standardized treadmill exercise. Biomarker concentrations and intracardiac pressures were measured at rest and after exercise. Hypotheses were tested using statistical methods. The level of significance was P < 0.05. ResultsHorses with MR showed increased left atrial (LA) and left ventricular (LV) dimensions but similar exercise capacity compared to healthy horses. Pulmonary capillary wedge pressures (PCWP) and CpANP increased with exercise. Horses with MR had higher PCWP and higher CpANP at rest and after exercise compared to healthy horses, with the maximum difference in CpANP reached 10 min after exercise. CpANP was significantly related to PCWP and – although inconsistently and only in healthy horses – to echocardiographic indices of LA and LV size and function. CpcTnI was low throughout the study in both groups. ConclusionsCpANP is increased in horses with MR and is related to LA pressures and to left heart dimensions. MR is not necessarily associated with exercise intolerance and exercise-induced myocardial stress or damage.

Conjugated equine estrogens and estradiol benzoate differentially modulate the natriuretic peptide system in spontaneously hypertensive rats

The purpose of this study was to compare the effects of conjugated equine estrogens (CEE) and estradiol benzoate on the blood pressure and body weight of spontaneously hypertensive rats (SHRs) and the associated changes in several components of the natriuretic peptide system. The blood pressure of randomly distributed female SHRs and Wistar rats was determined by tail plethysmography. The rats were ovariectomized and, after 3 weeks, injected daily for 4 days with estradiol benzoate (5 μg/100 g/d), CEE (50 μg/100 g/d), or vehicle (corn oil 0.1 mL/100 g/d). One day after the last injection, the rats were decapitated, and their blood was collected to measure atrial natriuretic peptide (ANP) and estradiol. The atria were removed to measure ANP levels using radioimmunoassay and to quantify ANP messenger RNA expression using real-time polymerase chain reaction. The kidneys and adipose tissue were removed to analyze the expression of natriuretic peptide clearance receptor messenger RNA. A reduction in blood pressure was observed in estradiol-treated SHRs, but CEE treatment had no effect. Estradiol decreased the body weight and parametrial adipose tissue mass of SHRs. Estradiol-induced alterations in SHRs were accompanied by increased synthesis and release of ANP. CEE had no effect on body weight but increased the mesenteric adipose tissue mass of SHRs. These results indicate that estradiol and CEE have different effects on the reduction in body weight and blood pressure. These results are correlated with changes in plasma ANP levels.