Natriuretic Peptide Release Research Articles

Natriuretic peptide release during exercise in patients with valvular heart disease: A systematic review.

Serum biomarkers have a potential role in the risk stratification of patients with heart valve disease and may help determine the optimal timing of intervention. Much of the published literature relates to biomarker sampling in a resting state, but the relationship of exercise biomarkers is less well described. We performed a systematic review to examine the significance of exercise natriuretic peptides on echocardiographic variables and cardiovascular events, in valvular heart disease. A search for studies that assessed exercise biomarkers in patients with moderate to severe valve lesions was performed. We examined the relationship between rest and exercise BNP and also the endpoints of symptoms, haemodynamic or echocardiographic variables and clinical outcomes. Eleven prospective studies were identified (844 participants). 61% were male and the mean age was 55.2 ± 9.6 years. The majority of the blood samples were taken at baseline and within 3 minutes of stopping exercise. There was a significant increase in exercise BNP compared with rest, in patients with aortic stenosis, mitral regurgitation and mitral stenosis. Elevated exercise BNP levels correlated with mean gradient and left atrial area, and there was a relationship between a higher exercise BNP and a blunted blood pressure response, in aortic stenosis. Furthermore, exercise BNP was independently associated with cardiac events, over and above resting values, in patients with mitral regurgitation and aortic stenosis. The results suggesting that exercise natriuretic peptide levels may have additive prognostic importance over resting levels, as well as demographic and echocardiographic data.

The chromogranin A1-373 fragment reveals how a single change in the protein sequence exerts strong cardioregulatory effects by engaging neuropilin-1.

Chromogranin A (CgA), a 439-residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA1-373 proangiogenic fragment. The present work investigated the possibility that human CgA1-373 influences the mammalian cardiac performance, evaluating the role of its C-terminal sequence. Haemodynamic assessment was performed on an ex vivo Langendorff rat heart model, while mechanistic studies were performed using perfused hearts, H9c2 cardiomyocytes and in silico. On the ex vivo heart, CgA1-373 elicited direct dose-dependent negative inotropism and vasodilation, while CgA1-372 , a fragment lacking the C-terminal R373 residue, was ineffective. Antibodies against the PGPQLR373 C-terminal sequence abrogated the CgA1-373 -dependent cardiac and coronary modulation. Ex vivo studies showed that CgA1-373 -dependent effects were mediated by endothelium, neuropilin-1 (NRP1) receptor, Akt/NO/Erk1,2 pathways, nitric oxide (NO) production and S-nitrosylation. In vitro experiments on H9c2 cardiomyocytes indicated that CgA1-373 also induced eNOS activation directly on the cardiomyocyte component by NRP1 targeting and NO involvement and provided beneficial action against isoproterenol-induced hypertrophy, by reducing the increase in cell surface area and brain natriuretic peptide (BNP) release. Molecular docking and all-atom molecular dynamics simulations strongly supported the hypothesis that the C-terminal R373 residue of CgA1-373 directly interacts with NRP1. These results suggest that CgA1-373 is a new cardioregulatory hormone and that the removal of R373 represents a critical switch for turning "off" its cardioregulatory activity.

Plasma NT-proBNP and pulmonary to systemic blood flow ratio in congenital heart defects with left-to-right shunts

Background Cardiac left-to-right shunts changes to the pulmonary-to-systemic blood flow ratio (Qp/Qs ratio). This ratio can be used to monitor the hemodynamics of the heart. Left-to right-shunts cause the release of amino terminal proB-ty natriuretic peptide (NT-proBNP) that can be utilized as a specific marker for the presence of heart failure in children with congenital heart defects (CHDs). Early intervention such as defect closure in CHD is important to prevent heart failure. 
 Objective To assess for a correlation between the level of NT pro-BNP and Qp/Qs ratio in CHD patients with left-to-right shunts.
 Methods This cross-sectional, analytical study was conducted in 32 children who underwent cardiac catheterization at Sanglah General Hospital, Denpasar, Bali, and were recruited by consecutive sampling. NT-proBNP levels were measured by ELISA with a two-step sandwich assay system; Qp/Qs ratio using Fick rules. Statistical analyses included Shapiro-Wilk test, descriptive analysis for subject characteristics, and Pearson’s correlation analysis. A P value of <0.05 was considered to be statistically significant. Age and defect size were analyzed as confounding factors by partial correlation test.
 Results The correlation value between NT-proBNP and Qp/Qs ratio was r=0.384 (P<0.05), after controlling for age and defect size as cofounding factors.
 Conclusion There is a weak positive correlation between NT-proBNP levels and pulmonary-to-systemic blood flow ratio in patients with left-to-right shunt, after controlling for age and defect size as confounding factors.

The Role of Oxytocin in Cardiovascular Protection.

The beneficial effects of oxytocin on infarct size and functional recovery of the ischemic reperfused heart are well documented. The mechanisms for this cardioprotection are not well defined. Evidence indicates that oxytocin treatment improves cardiac work, reduces apoptosis and inflammation, and increases scar vascularization. Oxytocin-mediated cytoprotection involves the production of cGMP stimulated by local release of atrial natriuretic peptide and synthesis of nitric oxide. Treatment with oxytocin reduces the expression of proinflammatory cytokines and reduces immune cell infiltration. Oxytocin also stimulates differentiation stem cells to cardiomyocyte lineages as well as generation of endothelial and smooth muscle cells, promoting angiogenesis. The beneficial actions of oxytocin may include the increase in glucose uptake by cardiomyocytes, reduction in cardiomyocyte hypertrophy, decrease in oxidative stress, and mitochondrial protection of several cell types. In cardiac and cellular models of ischemia and reperfusion, acute administration of oxytocin at the onset of reperfusion enhances cardiomyocyte viability and function by activating Pi3K and Akt phosphorylation and downstream cellular signaling. Reperfusion injury salvage kinase and signal transducer and activator of transcription proteins cardioprotective pathways are involved. Oxytocin is cardioprotective by reducing the inflammatory response and improving cardiovascular and metabolic function. Because of its pleiotropic nature, this peptide demonstrates a clear potential for the treatment of cardiovascular pathologies. In this review, we discuss the possible cellular mechanisms of action of oxytocin involved in cardioprotection.

Effect of insulin on natriuretic peptide gene expression in porcine heart

Gut hormones affect cardiac function and contractility. In this study, we examined whether insulin affects the cardiac atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression and release of proANP-derived peptides in pigs. Anaesthetized pigs were included in an experimental study comparing the effect of hyperinsulinemia in 15 pigs submitted to two different protocols versus 11 control pigs receiving saline infusion. Phosphorylation of Akt on Thr308 was determined by western blotting with a pAkt-Thr308 antibody. The mRNA contents of ANP and BNP were determined with real-time PCR; plasma and cardiac tissue proANP was measured with an immunoluminometric assay targeted against the mid-region of the propeptide and a processing-independent assay. Insulin stimulation increased phosphorylation of Akt Thr308 in both left atrium and left ventricle of porcine hearts (p < 0.005). No change was observed in ANP and BNP mRNA contents in the right or left atrium. BNP mRNA contents in the left ventricle, however, decreased 3-fold (p = 0.02) compared to control animals, whereas the BNP mRNA content in the right ventricle as well as ANP mRNA content in the right and left ventricle did not change following hyperinsulinemia. Moreover, the peptide contents did not change in the four cardiac chambers. Finally, proANP concentrations in plasma did not change during the insulin infusion compared to the control animals. These results suggest that insulin does not have direct effect on atrial natriuretic peptide expression but may have a role in the left ventricle.

Inflammation and Circulating Natriuretic Peptide Levels.

NPs (natriuretic peptides) are cardiac-derived hormones that promote natriuresis, diuresis, and vasodilation. Preclinical evidence suggests that nonhemodynamic triggers for NP release exist, with a few studies implicating inflammatory stimuli. We examined the association between inflammation and NP levels in humans. The associations between inflammation and NP levels were examined in 3 independent studies. First, in 5481 MESA (Multi-Ethnic Study of Atherosclerosis) participants, the cross-sectional (exam 1) and longitudinal (exams 1 to 3) associations between circulating IL6 (interleukin-6) and NT-proBNP (N terminal pro B-type natriuretic peptide) levels were examined in multivariable-adjusted models. Second, in a prospective study of 115 healthy individuals, changes in NP levels were quantified following exposure to lipopolysaccharide as an inflammatory stimulus. Third, in 13 435 hospitalized patients, the association between acute inflammatory conditions and circulating NP levels was assessed using multivariable-adjusted models. At the baseline MESA exam, each 1-unit higher natural log IL6 was associated with 16% higher NT-proBNP level ([95% CI, 10%-22%]; P=0.002). Each 1-unit higher baseline natural log IL6 level also associated with 6% higher NT-proBNP level ([95% CI, 1%-11%]; P=0.02) at 4-year follow-up. In the lipopolysaccharide study, median NT-proBNP levels rose from 21 pg/mL pre-lipopolysaccharide to 54 pg/mL post-lipopolysaccharide, P<0.001. In the hospitalized patient study, acute inflammatory conditions were associated with 36% higher NP levels ([95% CI, 17%-60%]; P<0.001). Inflammation appears to be associated with NP release. Interpretation of NP levels should therefore take into account inflammatory conditions.

MON-248 Tachycardia and Myocardial Injury Induced Natriuresis - a Rare Clinical Encounter

Introduction:Hyponatremia in the context of cerebral salt wasting secondary to intracranial events has well been described due to increased release of natriuretic peptides. We describe a case of natriuresis leading to acute symptomatic hyponatremia associated with tachyarrhythmia and myocardial infarction.Case:A 72-year-old lady was admitted with atrial fibrillation with rapid ventricular rate between 130-150 beats per minute, troponin positive chest pain, with high sensitivity troponin T of 1307 ng/L (<14 ng/L) and managed as type II myocardial infarction. 12 hours after admission she became acutely confused, agitated, associated with visual hallucinations and myoclonic jerks. On Examination she was dehydrated and there were no focal neurological features. Investigations showed acute hyponatremia with serum sodium (Na+) of 117 mmol/L (135 - 145 mmol/L) which 12 hours earlier, on admission, was 137 mmol/L, serum osmolarity 249 mosm/kg (275 - 295 mosm/kg), urine osmolarity 486 mosm/kg, urinary sodium of 160 mmol/L, pro-NTBNP 6575pg/ml (<450 pg/ml), 9am serum cortisol 575 nmol/L (140 - 690 nmol/L), TSH 4.72 mu/L (0.2 - 5.0 mu/L), FT4: 18.6pmol/L (10.0 - 24.0 pmol/L) and normal chest x-ray. She was treated with hypertonic saline (2.7%) 200ml followed by 0.9% saline infusion that corrected her serum sodium levels to 136 mmol/L over next 48-72 hours along with clinical symptoms gradually went back to normal. Repeat pro-NTBNP after recovery was 3153 pg/ml. Echocardiography showed normal left ventricular systolic function with normal atrial size and moderate mitral regurgitation with pulmonary artery pressure of 30mmHg. Based on acute onset hyponatremia and raised urinary sodium, we proposed diagnosis of hyponatremia secondary to salt wasting and we believe that in absence of acute intracranial pathology and raised pro-NTBNP, renal salt wasting was induced by acute rise in natriuretic peptides of cardiac origin either secondary to myocardial infarction or tachyarrhythmia. Paroxysmal SVT is a known cause of transient polyuria after termination but is not known to cause hyponatremia. Although well described in context of intracranial events, this is the first case of myocardial injury or tachyarrhythmia induced natriuresis leading to acute hyponatremia.Conclusion:Salt wasting due to natriuretic peptides is not exclusive to intracranial events. Any cardiac event leading to sudden increase in natriuretic peptides can lead to natriuresis which if prolonged enough can lead to acute symptomatic hyponatremia.Reference:1. Yee AH, Burns JD, Wijdicks EF. Cerebral Salt Wasting: Pathophysiology, Diagnosis, and Treatment. Neurosurgery Clinics of North America, 21(2), pp.339-352.2. Tan SY, Nolan J, Craig K, Swainson CP. Supraventricular tachycardia, right atrial pressure, atrial natriuretic peptide and polyuria—a necessary sequence? J Int Med 1993; 233: 415-17.

Stress-delta B-type Natriuretic Peptide Levels as a Test for Inducible Myocardial Ischemia: A Systematic Review and Meta-Analysis.

BackgroundCardiac ischemia induces myocardial dysfunction and ventricular wall stretch, which causes the release of B-type natriuretic peptide (BNP) into the bloodstream. However, it is unclear whether inducible ischemia produces a significant change in BNP levels (“stress delta-BNP”). The objective of this study was to determine the utility of stress-delta BNP levels and its precursor NT-proBNP for detecting inducible myocardial ischemia during cardiac stress testing.MethodsWe conducted a systematic review and meta-analysis. We searched PubMed, EMBASE, Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Ovid. Studies examining the changes in levels of BNP and its precursor, N-terminal pro-B-type natriuretic peptide (NT-proBNP), after an exercise cardiac stress test were included. Two reviewers independently analyzed titles and abstracts. s that did not provide enough information regarding eligibility criteria were kept for full-text evaluation. The same two reviewers also performed data extraction for analyses. Any disagreement was resolved by a consensus and, if it persisted, by a third reviewer adjudication. We report the median and mean values in studies in the order of sample size.ResultsA total of 15 studies met the inclusion criteria. Nine studies reported results in medians and six studies reported results in means. Of the nine studies, five assessed BNP alone, three assessed NT-proBNP, and one assessed both. Due to the non-normal distribution of results in these studies, they could not be meta-analyzed. Of the six studies that reported results in means, three assessed BNP and three assessed NT-proBNP. The standardized difference between normal and ischemic patients' stress-delta BNP values was -0.39 (95% confidence interval (CI): -0.61; -0.17) in a fixed-effects model and -0.73 (95% CI: -1.72; 0.28) in the random-effects model with high heterogeneity (I^2 = 94%, Q test P = 0.001). For NT-proBNP, the meta-analysis model showed no significant difference between the stress-delta test for ischemic and normal patients (standardized mean difference (SMD): -0.02, 95% CI: -0.31; 0.28). Patients without inducible ischemia appeared to have a lower baseline BNP and NT-proBNP compared to patients with inducible ischemia by stress testing. Although some studies report higher stress-delta BNP in the ischemic group, this pattern was not seen consistently across studies. There was high heterogeneity across studies which was not robust to sensitivity analysis. A random-effects model failed to find statistically significant differences in stress-delta BNP or NT-proBNP.ConclusionsWe failed to find a relationship between stress-delta BNP or NT-proBNP and the presence or absence of ischemia. This may be due to high heterogeneity in the underlying studies.

Intradermal Administration of Atrial Natriuretic Peptide Attenuates Cutaneous Vasodilation but Not Sweating in Young Men during Exercise in the Heat

Introduction: Prolonged exercise in the heat stimulates plasma release of atrial natriuretic peptide (ANP) in association with dehydration-induced reductions in blood volume. Elevated plasma ANP levels under these conditions may indirectly attenuate cutaneous blood flow and sweating responses due to the effects of this hormone on central blood volume and plasma osmolality and the resulting stimulation of nonthermal reflexes. However, it remains unclear whether cutaneous blood flow and sweating are directly modulated by ANP at the level of the cutaneous end organs (cutaneous microvessels and eccrine sweat glands) during prolonged exercise in the heat. Objective: Therefore, we evaluated the effects of local ANP administration on forearm cutaneous vascular conductance (CVC) and local sweat rate (LSR) during rest and exercise in the heat. Methods: In 9 habitually active young men (26 ± 6 years) CVC and LSR were evaluated at 3 intradermal microdialysis sites continuously perfused with lactated Ringer solution (control) or ANP (0.1 or 1.0 μM). Participants rested in a non-heat-stress condition (25°C) for approximately 60 min followed by 70 min in the heat (35°C). They then performed 50 min of moderate-intensity cycling (approx. 55% VO_{2 peak}), with a 30-min recovery. Thereafter, 50 mM sodium nitroprusside was administered at all sites to elicit maximum CVC, which was subsequently used to normalize all values (CVC_%max). Results: No effects of ANP on CVC_%max were observed in the non-heat-stress resting condition compared to the untreated control site (both p > 0.05). Conversely during rest in the heat there was an 11% (5–17%) reduction in CVC_%max at the 1.0 μM ANP site relative to the untreated control site (p < 0.05). At the end of exercise CVC_%max was attenuated by 12% (1–23%) at the 0.1 μM ANP site and by 21% (7–35%) at the 1.0 μM ANP site relative to the untreated control site (all p < 0.05). Conversely, neither concentration of ANP influenced sweating at any time point (all p > 0.05). Conclusion: Intradermal ANP administration directly attenuated cutaneous blood flow, but not sweating, in habitually active young men during rest and exercise in the heat.

Hypervolemia does not cause degradation of the endothelial glycocalyx layer during open hysterectomy performed under sevoflurane or propofol anesthesia.

Fluid-induced hypervolemia may stimulate the release of natriuretic peptides and cause degradation (shedding) of the endothelial glycocalyx layer. Sevoflurane is believed to protect the glycocalyx, but the importance of using sevoflurane to prevent shedding during routine surgery is unclear. The plasma concentrations of brain natriuretic peptide and two biomarkers of glycocalyx shedding, syndecan-1, and heparan sulfate, were measured in 26 patients randomized to receive general anesthesia with sevoflurane or propofol during open abdominal hysterectomy. The fluid therapy consisted of 25mL/kg (approximately 2 L) of Ringer´s lactate over 30minutes. Blood hemoglobin and plasma albumin were used to indicate plasma volume expansion and capillary leakage. The plasma concentrations of brain natriuretic peptide and shedding products showed low levels throughout the surgery (median brain natriuretic peptide, 21ng/L; syndecan-1, 12.9ng/mL; and heparan sulfate, 6.5µg/mL), but the heparan sulfate concentration increased 2hours post-operatively (to 17.3µg/mL, P<.005). No differences were noted between the propofol and sevoflurane groups in any of the measured parameters. Albumin was apparently recruited to the bloodstream during the first 20minutes, when the intravascular retention of infused fluid was almost 100%. The urine flow was <1mL/min, despite the vigorous volume loading. No relevant elevations of brain natriuretic peptide or degradation products of the glycocalyx layer were observed when hypervolemia was induced during open abdominal hysterectomy performed with sevoflurane or propofol anesthesia. Plasma volume expansion from Ringer´s lactate was pronounced.

ACUTE EFFECT OF DIFFERENT TYPES OF EXERCISE ON NATRIURETIC PEPTIDES OF WISTAR RATS

ABSTRACT Introduction: The study of the effects of different types of physical exercise on cardiovascular physiology is increasing in the literature. The many mechanisms of hemodynamic control include the atrial release of natriuretic peptides. Although extensive evidence demonstrates their acute effects and the increase in their plasma concentration, it is not known whether both atria respond in a similar way to both types of natriuretic peptide in response to different types of exercise. Objective: To compare the acute responses of different exercise types in the atrial (ANP) and brain (BNP) natriuretic peptides of both atrial cardiomyocytes of Wistar rats. Methods: Animals were divided into control (CG), aerobic (AG), resistance (RG) and combined (ARG). The RG performed six climbs, with a load equivalent to 60% of body weight. The AG ran on a treadmill at a speed of 12m/min for 60 minutes. The ARG exercise consisted of three consecutive ladder climbs, followed by 30 minutes of running. Results: First, the right atrium released more ANP and BNP during all types of exercise; second, the resistance exercise released the most ANP and BNP in both atria; third, in the right atrium, aerobic and combined workouts released more small and medium ANP granules while resistance exercise released larger BNP granules; and fourth, in the left atrium, aerobic exercise released more ANP granules while resistance and combined exercise released larger ANP and BNP granules. Conclusion: All types of exercise induce partial release of natriuretic peptide granules, with greater response to resistance exercise. Furthermore, a particular and different response could be seen in both types of atria in the release of ANP and BNP. Level of evidence II; Therapeutic studies - Investigation of treatment results.

IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis.

SummaryKawasaki disease (KD) vasculitis is an acute febrile illness of childhood characterized by systemic vasculitis of unknown origin, and is the most common cause of acquired heart disease among children in the United States. While histological evidence of myocarditis can be found in all patients with acute KD, only a minority of patients are clinically symptomatic and a subset demonstrate echocardiographic evidence of impaired myocardial function, as well as increased left ventricular mass, presumed to be due to myocardial edema and inflammation. Up to a third of KD patients fail to respond to first‐line therapy with intravenous immunoglobulin (IVIG), and the use of interleukin (IL)‐1 receptor antagonist (IL‐1Ra, anakinra) is currently being investigated as an alternative therapeutic approach to treat IVIG‐resistant patients. In this study, we sought to investigate the effect of IL‐1Ra on myocardial dysfunction and its relation to myocarditis development during KD vasculitis. We used the Lactobacillus casei cell‐wall extract (LCWE)‐induced murine model of KD vasculitis and investigated the effect of IL‐1Ra pretreatment on myocardial dysfunction during KD vasculitis by performing histological, magnetic resonance imaging (MRI) and echocardiographic evaluations. IL‐1Ra pretreatment significantly reduced KD‐induced myocardial inflammation and N‐terminal pro B‐type natriuretic peptide (NT‐proBNP) release. Both MRI and echocardiographic studies on LCWE‐injected KD mice demonstrated that IL‐1Ra pretreatment results in an improved ejection fraction and a normalized left ventricular function. These findings further support the potential beneficial effects of IL‐1Ra therapy in preventing the cardiovascular complications in acute KD patients, including the myocarditis and myocardial dysfunction associated with acute KD.

Renal Sympathetic Denervation Improves Outcomes in a Canine Myocardial Infarction Model.

BackgroundMyocardial infarction (MI) is the main cause of heart failure (HF), and sympathetic nerve activity is associated with prognosis chronic heart failure. Renal sympathetic denervation (RDN) is noted for its powerful effect on the inhibition of sympathetic nerve activity. This study investigated the effect of RDN on heart failure in dogs after myocardial infarction.Material/MethodsThe experimental animals were randomized into 2 groups: the MI group (n=12) and the sham operation group (n=6). In the MI group we established an MI model by permanently ligating the left anterior descending branch. After 4 weeks, the MI dogs were randomly divided into 2 groups: the MI+RDN group (MI+renal sympathetic denervation, n=6) and the simple MI group (n=6). Animals in the MI+RDN group underwent both surgical and chemical renal denervation.ResultsCompared with sham operation group, left ventricular fraction shortening (LVFS) and left ventricular ejection fraction (LVEF) were significantly reduced in the simple MI group, while the reduction was partly reversed in the MI+RDN group. RDN reduced sympathetic nerve activity and release of B-type natriuretic peptide (BNP) and Angiotensin II (AngII) in the MI+ RDN group but not in the simple MI group.ConclusionsCanine renal sympathetic denervation prevents myocardial malignant remodeling by lowering the activity of the systemic sympathetic nerve and inhibiting renin-angiotensin-aldosterone system (RASS) activation, providing a new target and method for the treatment of heart failure.

Role of SNAREs in Atopic Dermatitis–Related Cytokine Secretion and Skin-Nerve Communication

The role of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in atopic dermatitis (AD) is unknown. This study identifies the function of soluble N-ethylmaleimide sensitive factor attachment protein receptor in AD-related cytokine secretion and epidermis-nerve communication. Herein, we report that various cytokines were simultaneously upregulated and coreleased in innate immunity-activated primary human keratinocytes. AD-related cytokines thymic stromal lymphopoietin, endothelin-1, and inflammatory tumor necrosis factor-α activated distinct but overlapping sensory neurons. Tumor necrosis factor-α potentiated thymic stromal lymphopoietin-induced Ca2+-influx, whereas endothelin-1 caused itch-selective B-type natriuretic peptide release. In primary human keratinocytes, B-type natriuretic peptide upregulated genes promoting dermatological and neuroinflammatory diseases and conditions. VAMP3, SNAP-29, and syntaxin 4 proved important in driving cytokine release from primary human keratinocytes. Depletion of VAMP3 inhibited nearly all the cytokine release including thymic stromal lymphopoietin and endothelin-1. Accordingly, VAMP3 co-occurred with endothelin-1 in the skins of patients with AD. Our study pinpoints the pivotal role of soluble N-ethylmaleimide sensitive factor attachment protein receptors in mediating cytokine secretion related to AD. VAMP3 is identified as a suitable target for developing broad-spectrum anticytokine therapeutics for controlling itch and atopic skin inflammation.

INFLAMMATION AND CIRCULATING NATRIURETIC PEPTIDE LEVELS IN HUMANS

Natriuretic peptides (NPs) are cardiac derived hormones that promote natriuresis, diuresis, and vasodilation. Preclinical evidence suggests that non-hemodynamic triggers for NP release exist, with a few studies implicating inflammatory cytokines, e.g. interleukin-6 (IL6). The impact of inflammation

Nitric oxide acutely modulates hypothalamic and neurohypophyseal carbon monoxide and hydrogen sulphide production to control vasopressin, oxytocin and atrial natriuretic peptide release in rats.

Nitric oxide (NO) negatively modulates the secretion of vasopressin (AVP), oxytocin (OT) and atrial natriuretic peptide (ANP) induced by the increase in extracellular osmolality, whereas carbon monoxide (CO) and hydrogen sulphide (H2 S) act to potentiate it; however, little information is available for the osmotic challenge model about whether and how such gaseous systems modulate each other. Therefore, using an acute ex vivo model of hypothalamic and neurohypophyseal explants (obtained from male 6/7-week-old Wistar rats) under conditions of extracellular iso- and hypertonicity, we determined the effects of NO (600μmolL-1 sodium nitroprusside), CO (100μmolL-1 tricarbonylchloro[glycinato]ruthenium [II]) and H2 S (10mmolL-1 sodium sulphide) donors and nitric oxide synthase (NOS) (300μmolL-1 Nω -methyl-l-arginine [LNMMA]), haeme oxygenase (HO) (200μmolL-1 Zn(II) deuteroporphyrin IX 2,4-bis-ethylene glycol [ZnDPBG]) and cystathionine β-synthase (CBS) (100μmolL-1 aminooxyacetate [AOA]) inhibitors on the release of hypothalamic ANP and hypothalamic and neurohypophyseal AVP and OT, as well as on the activities of NOS, HO and CBS. LNMMA reversed hyperosmolality-induced NOS activity, and enhanced hormonal release by the hypothalamus and neurohypophysis, in addition to increasing CBS and hypothalamic HO activity. AOA decreased hypothalamic and neurohypophyseal CBS activity and hormonal release, whereas ZnDPBG inhibited HO activity and hypothalamic hormone release; however, in both cases, AOA did not modulate NOS and HO activity and ZnDPBG did not affect NOS and CBS activity. Thus, our data indicate that, although endogenous CO and H2 S positively modulate AVP, OT and ANP release, only NO plays a concomitant role of modulator of hormonal release and CBS activity in the hypothalamus and neurohypophysis and that of HO activity in the hypothalamus during an acute osmotic stimulus, which suggests that NO is a key gaseous controller of the neuroendocrine system.

Endurance exercise training attenuates natriuretic peptide release during maximal effort exercise: biochemical correlates of the "athlete's heart".

Endurance exercise training (ET) stimulates eccentric left ventricular hypertrophy (LVH) with left atrial dilation. To date, the biochemical correlates of exercise-induced cardiac remodeling (EICR) remain incompletely understood. Collegiate male rowers (n = 9) were studied with echocardiography and maximal-effort cardiopulmonary exercise testing (MECPET) before and after 90 days of ET intensification. Midregional proatrial natriuretic peptide (MR-proANP), NH2-terminal pro B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T were measured at rest, peak MECPET, and 60 min post-MECPET at both study time points. Endurance exercise training resulted in eccentric LVH (LV mass = 102 ± 8 vs. 110 ± 11 g/m2, P = 0.001; relative wall thickness = 0.36 ± 0.04 vs. 0.37 ± 0.04, P = 0.103), left atrial dilation (74 ± 18 vs. 84 ± 15 ml, P < 0.001), and increased exercise capacity (peak V̇o2 = 53.0 ± 5.9 vs. 67.3 ± 8.2 ml·kg-1·min-1, P < 0.001). Left ventricular remodeling was characterized by an ~7% increase in LV wall thickness but only a 3% increase in LV chamber radius. The magnitude of natriuretic peptide release, examined as percent change from rest to peak exercise, was significantly lower for both MR-proANP (115 [95,127]% vs. 78 [59,87]%, P = 0.04) and NT-proBNP (46 [31,70]% vs. 27 [25,37]%, P = 0.02) after ET. Rowing-based ET and corollary EICR appear to result in an attenuated natriuretic peptide response to maximal effort exercise. This may occur as a function of decreased cardiac wall stress after ET as seen by disproportionally higher ventricular wall thickening compared with chamber dilation.NEW & NOTEWORTHY Using longitudinal pre- and postendurance training natriuretic peptide measurements, we demonstrate that the development of exercise-induced cardiac remodeling results in an attenuated natriuretic peptide response to acute bouts of maximal intensity exercise. Exercise-induced cardiac remodeling was associated with a disproportionally higher ventricular wall thickening compared with chamber dilation, a pattern that reduces cardiac wall stress. These observations advance our understanding of both the structural and biochemical adaptations that underlie the cardiovascular response to endurance training.

Abstract P379: Paradoxical Natriuretic Peptide Resetting in Astronauts

Human studies in space provide unique and often unexpected findings regarding the role of terrestrial gravity for human cardiovascular and renal regulation. While vascular volume is shifted towards the head, which would be expected to increase natriuretic peptide (NP) release, preliminary observations suggested the opposite. Therefore, we assessed natriuretic peptide regulation on different controlled sodium diets in space and on Earth. Eight male astronauts (50±2.8 yrs.) ingested higher (5.5 g/day) and low sodium (2g/day) diets for five days each on Earth and on the International Space Station (ISS) in alternating order. Dietary nutrient intake was individually tailored and kept constant. At day five of each intervention, midregional-pro atrial NP (MRproANP), N-terminal pro B-type NP (NTproBNP), and aldosterone in blood, urinary sodium excretion, and body mass were measured. On Earth, MRproANP was 71.86±4.39 pmol/L on moderately high and 65.13±6.71 pmol/L on low sodium intake. In space, MRproANP was 44.61±4.26 pmol/L on high and 31.37±4.02 pmol/L on low sodium intake (p&lt;0.001 between sodium intakes, p&lt;0.01 between Earth and space). Similarly, NTproBNP responded to changes in sodium intake (p&lt;0.001) and was regulated at lower levels in space (p=0.008). Serum aldosterone concentrations decreased on higher sodium intake but did not differ between space and Earth (p&lt;0.001 between sodium intakes, p=0.95 between Earth and space). Body mass did not differ between low and high sodium intake, either on Earth or in space (space: low sodium 83.7±3.1 kg, higher sodium 84.4±3.1 kg, Earth: low sodium 87.1±3.6 kg, higher sodium 87.2±3.2 kg). In conclusion, NP release while responding to changes in sodium intake is paradoxically reset to lower levels in space. The mechanisms may have implications for volume regulation and cardiovascular health during long-term space travel.

Glucotoxicity results in apoptosis in H9c2 cells via alteration in redox homeostasis linked mitochondrial dynamics and polyol pathway and possible reversal with cinnamic acid

Several mechanisms have been proposed for the heart dysfunction during hyperglycemia. The aim of the present in vitro study is to elucidate the role of alterations in redox homeostasis in the induction of apoptosis during hyperglycemia in H9c2 cells via dysfunction in mitochondria and polyol pathway and evaluation of the beneficial effect of cinnamic acid against the same. The H9c2 cells were incubated with 33 mM glucose for 48 h to simulate the diabetic condition. Cell injury was confirmed with a significant increase of atrial natriuretic peptide and lactate dehydrogenase release. Alterations in the innate antioxidant system, polyol pathway, mitochondrial integrity, dynamics and apoptosis were investigated. Hyperglycemic insult has significantly affected redox homeostasis via depletion of superoxide dismutase, glutathione and enhanced reactive oxygen species generation. It also caused dysregulation in mitochondrial dynamics (fusion, fission proteins), dissipation of mitochondrial transmembrane potential and increased sorbitol accumulation. Finally, apoptosis was observed with upregulation of Bax, activation of caspase-3 and downregulation of Bcl-2. Cinnamic acid cotreatment increased the innate antioxidant status, improved mitochondrial function and prevented apoptosis in H9c2 cardiomyoblasts. Moreover, this in vitro model is found to be ideal for the elucidation of mechanisms at the cellular and molecular level of any physiological, pharmacological and toxicological incidents in H9c2 cells.

NT-proBNP and CA 125 levels are associated with increased pro-inflammatory cytokines in coronary sinus serum of patients with chronic heart failure

PurposeHeart failure (HF) is considered to be a complex syndrome associated with neurohormonal and cytokine activation, that contribute to its progression. There are evidences which showed that, carbohydrate antigen 125 (CA 125), a tumor marker widely used for ovarian cancer therapy monitoring, was significantly elevated in HF patients. We hypothesized that inflammatory stimuli may be responsible for amino-terminal fragment of the prohormone B-type natriuretic peptide (NT-proBNP) and CA-125 production and release in chronic HF (CHF). We aimed to measure the levels of NT-proBNP, CA 125, pro-anti-inflammatory cytokines (IL-6, IL-1β, IL-8, TNF-α and IL-4), from peripheral venous (PV) and coronary sinus (CS) blood samples, in patients with CHF and to assess their correlation with echocardiographic indices. MethodsWe enrolled 32 subjects (20M/12F) with CHF (III-IV NYHA functional class) who were to undergo cardiac resynchronization therapy (CRT) device implantation and 30 healthy controls (18M/12F). Two blood samples, from PV and CS, were collected at the time of CRT for each CHF patient. Serum levels of biomarkers were measured by ELISA. Cardiac function was assessed echocardiographically. ResultsAll investigated biomarkers were significantly higher in CHF patients than in non-CHF controls (P < 0.001). There were positive correlations between biomarkers concentrations in PV and CS (r between 0.54 and 0.98, all P < 0.003). NT-proBNP, IL-6 and IL-1β levels were 17%, 86% and 36% higher in CS than in PV, these increases being very well correlated each other, while CA 125 levels were 86% higher in PV than in CS. Moreover, CS NT-proBNP, CS IL-6 and CS IL-1β serum concentrations were inversely related to the echocardiographically determined left ventricular ejection fraction (LVEF) (r = −0.61, P < 0.001; r = −0.71, P < 0.001 and r = −0.48, P = 0.005, respectively). A positive relationship was found between CA 125 and IL-1β (r = 0.51, P = 0.003) in CS serum and between CA 125 and IL-6 (r = 0.43, P = 0.015), TNF-α (r = 0.46, P = 0.008) in PV serum. CA 125 concentrations were closely related to NT-proBNP both in CS (r = 0.46, P = 0.008) and PV (r = 0.52, P = 0.002). ConclusionsCS sampling of NT-proBNP, CA 125 and pro-anti-inflammatory cytokines provides an additional insight into the possible mechanisms by which these biomarkers lead to left ventricular remodeling. Our results clearly suggest that serum NT-proBNP and CA 125 levels not only in PV, but also in CS of patients with CHF, may be dependent on inflammation as a consequence of cytokine network activation.