Administration Of Atrial Natriuretic Peptide Research Articles

Atrial natriuretic peptide protects against gut barrier injury through PLC-γ1/ROS feedback loop in rats following traumatic hemorrhagic shock

Introduction The mechanisms underlying the protective effects of atrial natriuretic peptide (ANP) on the gut barrier during traumatic hemorrhagic shock (THS) remain elusive. This study aimed to explore the potential role of ANP in safeguarding against gut barrier dysfunction after THS, focusing on the PLC-γ1/ROS feedback loop. Methods In our THS rat model, we randomly allocated male Sprague-Dawley rats to receive intravenous ANP with or without a concurrent NADPH oxidase/p38 MAPK inhibitor during the shock phase. After 24 h, we assessed circulatory and jejunal ANP, ROS, intestinal tight junction proteins, and apoptosis to evaluate the effects of ANP on the gut barrier and its interplay with intestinal ANP and ROS. Rat small intestinal epithelial cells (IECs) were also treated with ANP and subjected to hypoxia/re-oxygenation injury, with or without PI3K/PLC inhibition, to elucidate the relationship between ANP/ROS signaling and PLC-γ1. Furthermore, we modulated PLC-γ1 expression in these IECs to examine its impact on ROS and ANP production. Results Intravenous ANP administration at 0.025 μg/kg/min during THS significantly increased intestinal ANP and ROS levels at 24 h. ANP treatment enhanced the expression of intestinal tight junction proteins and reduced IEC apoptosis. Inhibition of circulatory ROS diminished intestinal ANP levels, while suppression of circulatory ANP led to a reduction in intestinal ROS. Decreasing PLC-γ1 expression in hypoxia/re-oxygenation-treated IECs resulted in lower ROS and ANP levels, whereas augmenting PLC-γ1 expression did not alter these levels. Additionally, PI3K inhibition markedly decreased PLC-γ1 expression in these cells. Conclusion ANP-induced protection of the intestinal barrier in THS is mediated by an intrinsic PLC-γ1/ROS positive feedback loop. ANP preserves gut barrier integrity and reduces IEC apoptosis through this mechanism. Further studies are warranted to investigate the interaction between IECs and other cellular components within the PLC-γ1/ROS loop.

Endocrinological disorders in acute kidney injury: an often overlooked field of clinical research.

Acute kidney injury (AKI) is a common comorbidity, affecting approximately one in five hospitalized adults. The kidney is the site for the production, metabolism or excretion of most hormones, including the production of erythropoietin (EPO), the active form of vitamin D, renin, thrombopoietin, and the excretion of insulin, catecholamines, gastrin and many other hormones. Therefore, it is reasonable to say that AKI can have a considerable impact on the endocrine system. Although the effects of AKI on various parameters, including cardiovascular parameters, serum electrolytes and acid-base disorders, neuro-humoral mechanisms and neurological outcomes have been extensively studied, the endocrinological consequences of AKI are understudied. Thyroid dysfunction, mainly euthyroid sick syndrome, hypo/hyperglycemia, bone mineral disorders, changes in EPO and atrial natriuretic peptide (ANP) levels are commonly found in AKI. EPO, thyroxine and ANP administration have been evaluated as potential tools to prevent or treat AKI with varying success, while the effects of AKI on some key hormones, including cortisol and insulin, have never been studied. Aim of this narrative review is to illustrate what is known and what is not known about the endocrinological outcomes of AKI. Few clinical trials are ongoing: however, there is a clear need for large-scale randomized controlled trials investigating the endocrinological consequences of AKI.

Effects and safety of natriuretic peptides as treatment of cirrhotic ascites: A systematic review and meta-analysis.

BACKGROUNDNatriuretic peptides are involved in the cascade of pathophysiological events occurring in liver cirrhosis, counterbalancing vasoconstriction and anti-natriuretic factors. The effects of natriuretic peptides as treatment of cirrhotic ascites have been investigated only in small studies, and definitive results are lacking.AIMTo examine the effects and safety of natriuretic peptides in cirrhosis patients with ascites.METHODSWe searched MEDLINE, Web of Science, Scopus, Cochrane Library and Embase for all available studies applying intravenous administration of any natriuretic peptide to patients suffering from cirrhotic ascites. Inclusion was not limited by treatment duration or dose, or by follow-up duration. Both randomised controlled trials and non-randomised studies were eligible for inclusion. The primary outcome was change in renal sodium excretion. Secondary outcomes included safety measures and changes in renal water excretion, plasma aldosterone concentration, and plasma renin activity.RESULTSTwenty-two studies were included. Atrial natriuretic peptide (ANP) was the only intensively studied treatment. Sodium excretion increased in response to continuous ANP infusion and was more pronounced when infusion rates of > 30 ng/kg/min were administered compared with ≤ 30 ng/kg/min (P < 0.01). Moreover, natriuresis was significantly higher in study subgroups with mild/moderate ascites compared with moderate/severe and refractory ascites (P < 0.01). ANP infusions increased renal water excretion, although without reaching a statistically significant dose-response gradient. Plasma aldosterone concentration and plasma renin activity were significantly lower at baseline in study subgroups achieving a negative sodium balance in response to an ANP administration compared with treatment non-responders (P < 0.01). Blood pressure decreases occurred less frequently when ANP doses ≤ 30 ng/kg/min were applied. The quality of evidence for a natriuretic response to ANP was low, mainly due to small sample sizes and considerable between-study heterogeneity. Data were sparse for the other natriuretic peptides; B-type natriuretic peptide and urodilatin.CONCLUSIONIntravenous ANP infusions increase sodium excretion in patients with cirrhotic ascites. Continuous infusion rates > 30 ng/kg/min are the most effective. However, safety increases with infusion rates ≤ 30 ng/kg/min.

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling.

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Atrial natriuretic peptide (ANP): A novel mechanism for reducing ethanol consumption and seeking behaviors in female alcohol preferring (P) rats

Atrial Naturietic Peptide (ANP) is a neuropeptide that regulates function of the hypothalamic-pituitary-adrenal (HPA) axis, immune and neuroimmune system, and epigenetic factors. Research has indicated that ANP may mediate alcohol intake, withdrawal, and craving like behaviors. ANP receptors are present in the mesocorticolimbic (MCL) reward pathway of the brain, which includes the nucleus accumbens (Acb) and the ventral tegmental area (VTA). The objectives of the present study were to examine the effects of ANP microinjected into Acb subregions (Shell (Sh), Core (Co), ventral to AcbSh) on operant ethanol (EtOH) self-administration and into posterior VTA (pVTA) on EtOH-seeking behavior of female alcohol-preferring (P) rats. In the first experiment, ANP (0, 10 μg, or 100 μg) was microinjected into subregions of the Acb to determine its effects on EtOH self-administration. In the second experiment, ANP was microinjected into pVTA to determine its effects on Pavlovian Spontaneous Recovery (PSR) of responding, a measure of context-induced EtOH-seeking behavior. Administration of ANP directly into the AcbSh significantly reduced EtOH self-administration compared to vehicle, whereas ANP into the AcbCo or areas directly ventral to the AcbSh did not alter responding for EtOH. Microinjection of ANP into the pVTA significantly reduced responding on the EtOH-associated lever during the PSR test. The data indicate that activation of ANP systems in the (a) AcbSh can inhibit EtOH intake, and (b) in the pVTA can inhibit EtOH-seeking behavior. The results suggest that manipulations of the ANP system could be a potential target for pharmacotherapeutic intervention to treat alcohol use disorder. Supported in part by AA07462, AA07611, AA10717, AA10721, AA013522, AA019366, AA020908, AA022287, and AA024612.

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.

Effects of ANP on pulmonary vein electrophysiology, Ca2+ homeostasis and adrenergic arrhythmogenesis via PKA.

Atrial fibrillation (AF) is the most common form of arrhythmia and increases the risk of stroke and heart failure (HF). Pulmonary veins (PVs) are important sources of triggers that generate AF, and calcium (Ca2+ ) overload participates in PV arrhythmogenesis. Neurohormonal activation is an important cause of AF. Higher atrial natriuretic peptide (ANP) level predicts paroxysmal AF occurrence in HF patients. However, it is not clear if ANP directly modulates electrophysiological characteristics and Ca2+ homeostasis in the PVs. Conventional microelectrodes, whole-cell patch-clamp, and the Fluo-3 fluorimetric ratio technique were performed using isolated rabbit PV preparations or single isolated PV cardiomyocytes before and after ANP administration. We found that ANP (1, 10, and 100nmol/L) concentration-dependently decreased spontaneous activity in PV preparations. ANP (100nmol/L) decreased isoproterenol (1μmol/L)-induced PV spontaneous activity and burst firing. AP811 (100nmol/L, NPR-C agonist), H89 (1μmol/L, PKA inhibitor) decreased isoproterenol-induced PV spontaneous activity or burst firing, but successive administration of ANP had no further effect on PV activity. KT5823 (1μmol/L, PKG inhibitor) decreased isoproterenol-induced PV spontaneous activity but did not change isoproterenol-induced PV burst firing, whereas successive administration of ANP did not change isoproterenol-induced PV burst firing. ANP decreased intracellular Ca2+ transient and sarcoplasmic reticulum Ca2+ content in single PV cardiomyocytes. ANP decreased the late sodium current, L-type Ca2+ current, but did not change nickel-sensitive Na+ -Ca2+ exchanger current in single PV cardiomyocytes. In conclusion, ANP directly regulates PV electrophysiological characteristics and Ca2+ homeostasis and attenuates isoproterenol-induced arrhythmogenesis through NPR-C/cAMP/PKA signal pathway.

Cardiovascular Pleiotropic Effects of Natriuretic Peptides.

Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water–salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.

A Case of Spontaneous Regression of Pulmonary Small Cell Carcinoma

An 82-year-old man was examined using chest computed tomography after treatment for pneumonia. Imaging showed a nodular shadow in the left lower lobe with associated enlarged lymph nodes. A polypoid tumour was observed on bronchoscopic examination, and the histological findings showed pulmonary small cell carcinoma with infiltration of CD3-positive and CD8-positive lymphocytes. The patient declined any antitumoural therapy and experienced an exacerbation of heart failure treated with atrial natriuretic peptide. Eighteen months after the diagnosis, the polypoid tumour had disappeared. T lymphocyte-mediated immunity and the antitumoural effects of atrial natriuretic peptide may have influenced the observed spontaneous regression.LEARNING POINTSSpontaneous regression of pulmonary small cell carcinoma is an exceptional phenomenon.T lymphocyte-mediated immunity and the administration of atrial natriuretic peptide may have affected the observed spontaneous regression of pulmonary small cell carcinoma.

Atrial natriuretic peptide exerts hypotensive effect via regulator of G-protein signaling 2-mediated endothelial hyperpolarization

Objective: Atrial natriuretic peptide (ANP) functions via guanylyl cyclase (GC)-A, a single transmembrane receptor, resulting in diuresis, natriuresis, and lowering of blood pressure. However, molecular mechanism of hypotensive effect of ANP is not well understood. Results: Immunohistochemistry indicated that GC-A is abundantly expressed in endothelial cells. Intravenous infusion of ANP in wild-type mice significantly lowed systolic blood pressure. ANP failed to lowering systolic blood pressure in endothelial cell-specific GC-A knockout mice. In endothelial nitric oxide synthase knockout mice, ANP also significantly lowed systolic blood pressure. In in vitro study, ANP treatment significantly hyperpolarized cultured human umbilical vein endothelial cells (HUVECs), but not changed intracellular Ca2+ concentration in HUVECs. ANP-induced hyperpolarize of HUVECs was dependent of cyclic GMP-Protein Kinase G and regulator of G-protein signaling2 (RGS2) pathway but not dependent of Ca2-activated K+ channels. Conclusions: These results suggest that hypotensive effect of acute ANP administration can be caused by endothelial GC-A-mediated RGS2 pathway-dependent endothelial hyperpolarization.

Administration of Atrial Natriuretic Peptide Does Not Modulate Sweating or Cutaneous Vasodilation in Young Men Exercising in the Heat

Atrial natriuretic peptide (ANP) is a hormone secreted by cardiac muscle cells in response to increases in right atrial pressure, which can occur due to changes in blood pressure and blood volume. This hormone is also secreted during acute exercise in both temperate and hot environments and may be released into the blood due to the effects of increased venous return on the heart caused by active muscle contraction under these conditions. However, ANP release is diminished during prolonged exercise, which may ultimately impair heat loss if its release is linked to alterations in cutaneous blood flow and sweating. The current evidence is mixed with respect to a direct role of ANP in modulating cutaneous vasodilation and sweating responses, with some studies demonstrating an effect of exogenous ANP infusion in augmenting these heat loss responses, while others have failed to show any influence of the hormone. Thus, the purpose of this study was to evaluate the effects of intradermal administration of varying doses of ANP on cutaneous vasodilation and sweating responses in healthy habitually active young men exercising in a hot environment. Ten healthy young males (27 ± 6 years) exercised for 50 min at ~55% VO2peak in the heat (35°C, 20% relative humidity). Cutaneous vascular conductance (CVC, measured via laser Doppler flowmetry) and sweating (measured via ventilated capsules) were assessed at four dorsal forearm skin sites receiving either lactated Ringer's solution (Control) or one of three ANP doses (0.1 μM, 1.0 μM, 10 μM) via microdialysis. At the end of exercise, CVC was not different between Control (73 ± 14% CVCmax) and 0.1 μM (66 ± 20% CVCmax), 1.0 μM (69 ± 21% CVCmax), or 10 μM (71 ± 18% CVCmax) ANP sites (all P &gt; 0.05). Similarly, sweat rates were not different between Control (1.37 ± 0.43 mg/min/cm2) and 0.1 μM (1.43 ± 0.55 mg/min/cm2), 1.0 μM (1.44 ± 0.41 mg/min/cm2), or 10 μM (1.36 ± 0.37 mg/min/cm2) ANP sites (all P &gt; 0.05). In summary, these results demonstrate that in healthy habitually active young men, intradermal administration of ANP does not augment cutaneous vasodilation or sweating during exercise in the heat. Such findings may indicate that ANP does not have a direct effect on these heat loss responses. Alternatively, it may be the case that endogenous levels of ANP produced under these conditions are sufficient to elicit a maximal effect of the hormone on cutaneous blood flow and sweating in healthy young men, thus masking any direct effects of exogenous administration.Support or Funding InformationFunding support: Canadian Institutes of Health Research (held by Dr. Kenny).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Protective Effects of Atrial Natriuretic Peptide Infusion in Salt‐Sensitive Hypertension

Atrial Natriuretic Peptide (ANP) is a hormone secreted by cardiomyocytes in response to increased atrial volume; it stimulates water and sodium excretion by the kidneys and relieves pressure on the circulatory system. In our previous studies we compared wild type Dahl Salt Sensitive (SS) rats to SS rats lacking the Nppa gene which encodes ANP (SSNppa−/−). The data revealed that salt‐induced blood pressure development was significantly exacerbated in the SSNppa−/− rats. Furthermore, SSNppa−/− rats exhibited reduced urinary sodium excretion and diuresis, as well as aggravated kidney damage compared to wild type controls (FASEB J 2017 31:855.8.). These data led to a hypothesis that ANP infusion can have beneficial effects during the development of salt‐induced hypertension.Dahl SS rats were fed a high salt diet (HS, 4% NaCl) for 21 days, with a continuous i.v. infusion of ANP (100 ng/kg/day) administered from day 0 or day 14 onward to test preventive and therapeutic effects of ANP, respectively. Blood pressure was monitored throughout the study, and urine samples were collected in metabolic cages on days 0 and 21. At the end of the protocol animals were sacrificed and kidney tissues were harvested and stained with Masson's trichrome to evaluate renal damage. Fibrosis, glomerular injury, and protein casts formation were assessed; urine and plasma samples were also analyzed to estimate electrolyte homeostasis.ANP infusion had beneficial effects on BP and renal function compared to control animals. We observed a decrease in blood pressure in both groups infused with ANP during 0–21 days (21D) and 14–21 days (7D) of a HS challenge. Kidney to body weight ratio did not differ between the groups; however, we observed a trend for reduced renal hypertrophy in the 21D animals. Metabolic cage studies revealed no changes in diuresis; urinary electrolyte analysis showed a more effective sodium excretion in the 21D rats. Assessment of kidney damage demonstrated a decrease in protein casts in both 7D and 21D rats: 3.8% ± 0.47%, 2.7% ± 0.24%, and 2.0% ± 0.41% of the tissue surface in the control, 7D and 21D groups, respectively. Glomerular injury had a similar pattern: scores were 2.86 ± 0.09, 2.62 ± 0.07, and 2.41 ± 0.06. Renal fibrosis was alleviated in the 21D group (1.4% ± 0.18%, compared to 1.9% ± 0.49% and 3.1% ± 0.31% in the 7D and control groups).Therefore, ANP infusion had both preventive and therapeutic effects. Our data revealed that ANP administration during the HS diet challenge resulted in decreased blood pressure, increased electrolyte excretion, and reduced tissue damage.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Atrial natriuretic peptide accelerates human endothelial progenitor cell-stimulated cutaneous wound healing and angiogenesis.

Atrial natriuretic peptide (ANP) is a powerful vasodilating peptide secreted by cardiac muscle cells, and endothelial progenitor cells (EPCs) have been reported to stimulate cutaneous wound healing by mediating angiogenesis. To determine whether ANP can promote the EPC-mediated repair of injured tissues, we examined the effects of ANP on the angiogenic properties of EPCs and on cutaneous wound healing. In vitro, ANP treatment enhanced the migration, proliferation, and endothelial tube-forming abilities of EPCs. Furthermore, small interfering RNA-mediated silencing of natriuretic peptide receptor-1, which is a receptor for ANP, abrogated ANP-induced migration, tube formation, and proliferation of EPCs. In a murine cutaneous wound model, administration of either ANP or EPCs had no significant effect on cutaneous wound healing or angiogenesis in vivo, whereas the coadministration of ANP and EPCs synergistically potentiated wound healing and angiogenesis. In addition, ANP promoted the survival and incorporation of transplanted EPCs into newly formed blood vessels in wounds. These results suggest ANP accelerates EPC-mediated cutaneous wound healing by promoting the angiogenic properties and survival of transplanted EPCs.

Atrial Natriuretic Peptide: A Potential Early Therapy for the Prevention of Multiple Organ Dysfunction Syndrome Following Severe Trauma.

Trauma remains a tremendous medical burden partly because of increased expenditure for the management of multiple organ dysfunction syndrome (MODS) developed during hospital stay. The intestinal barrier injury continues to be a second insult resulting in MODS which currently lacks efficient strategies for prevention. Recent studies have uncovered multi-organ protective benefits of atrial natriuretic peptide (ANP) in cardiovascular disease. However, the role of ANP in the prevention of MODS following severe trauma has not been understood. In our laboratory study, 1-h infusion of exogenous ANP during hemorrhagic shock following severe trauma induced high-level expression of endogenous serum ANP after 24 h, this effect was related to the improved level of functional biomarkers in multiple organs. Such phenomenon has not been found in other laboratories. A thorough literature review consequently was performed to uncover the potential mechanisms, to appraise therapy safety, and to propose uncertainties. In severe trauma, short-term exogenous ANP therapy during hemorrhagic shock may promote sustained endogenous expression of ANP from intestinal epithelium through activating a positive feedback loop mechanism involving phospholipase C-γ1 and reactive oxygen species crosstalk. This feedback loop may prevent MODS through multiple signaling pathways. Administration of ANP during hemorrhagic shock is thought to be safe. Further studies are required to confirm our proposed mechanisms and to investigate the dose, duration, and timing of ANP therapy in severe trauma.

Transcriptome analysis reveals a role for the endothelial ANP-GC-A signaling in interfering with pre-metastatic niche formation by solid cancers.

Cancer establishes a microenvironment called the pre-metastatic niche in distant organs where disseminated cancer cells can efficiently metastasize. Pre-metastatic niche formation requires various genetic factors. Previous studies suggest that inhibiting a single niche-factor is insufficient to completely block pre-metastatic niche formation especially in human patients. Here we show that the atrial natriuretic peptide (ANP), an endogenous hormone produced by the heart, inhibits pre-metastatic niche formation and metastasis of murine solid cancer models when pharmacologically supplied in vivo. On the basis of a wealth of comprehensive RNA-seq data, we demonstrated that ANP globally suppressed expression of cancer-induced genes including known niche-factors in the lung. The lungs of mice overexpressing GC-A, a receptor for ANP in endothelial cells, were conferred resistance against pre-metastatic niche formation. Importantly, neither ANP administration nor GC-A overexpression had a detrimental effect on lung gene expression in a cancer-free condition. The current study establishes endothelial ANP-GC-A signaling as a therapeutic target to control the pre-metastatic niche.

A multicenter randomized controlled trial of surgery alone or surgery with atrial natriuretic peptide in lung cancer surgery: study protocol for a randomized controlled trial

BackgroundPostoperative cancer recurrence is a major problem following curative surgery. In a previous retrospective study of lung cancer surgery, we reported that administration of atrial natriuretic peptide (ANP) during the perioperative period reduced postoperative recurrence. We demonstrated that ANP inhibited the adhesion of cancer cells to vascular endothelium as a vasoprotective action. The objective of this study is to evaluate the effects of ANP on the incidence of postoperative cancer recurrence in lung cancer surgery.Methods/designThe present study is a multicenter, randomized trial with two parallel groups of patients with lung cancer comparing surgery alone and surgery with ANP administration for 3 days during the perioperative period. A total of 500 patients will be enrolled from 10 Japanese institutions. The primary endpoint is 2-year relapse-free survival (RFS). The secondary endpoints are 2-year cancer-specific RFS, 5-year RFS, overall survival, the incidence of postoperative complications, and the completion rate of ANP treatment.DiscussionThe principal question addressed in this trial is whether ANP with its vasoprotective action can reduce cancer recurrence following lung cancer surgery.Trial registrationUMIN Clinical Trials Registry identifier: UMIN000018480. Registered on 31 July 2015.

Impact of decreased serum albumin levels on acute kidney injury in patients with acute decompensated heart failure: a potential association of atrial natriuretic peptide.

Although hypoalbuminemia at admission is a risk for acute kidney injury (AKI) and mortality in patients with acute decompensated heart failure (ADHF), the clinical significance of decreased serum albumin levels (DAL) during ADHF therapy has not been elucidated. This study aimed to evaluate whether DAL was associated with AKI, and whether intravenous atrial natriuretic peptide (ANP) administration, which provides an effective treatment for ADHF but promotes albumin extravasation, was associated with DAL and AKI. A total of 231 consecutive patients with ADHF were enrolled. AKI was defined as ≥0.3mg/dl absolute or 1.5-fold increase in serum creatinine levels within 48h. AKI occurred in 73 (32%) of the 231 patients during ADHF therapy. The median value of decreases in serum albumin levels was 0.3g/dl at 7days after admission. When DAL was defined as ≥0.3g/dl decrease in serum albumin levels, DAL occurred in 113 patients, and was independently associated with AKI. Of the 231 patients, 73 (32%) were treated with intravenous ANP. DAL occurred more frequently in patients receiving ANP than in those not receiving ANP (77 vs. 36%, p < 0.001), and ANP was independently associated with DAL. The incidence of AKI was higher in patients receiving ANP than in those not receiving ANP (48 vs. 24%, p < 0.001). ANP was independently associated with AKI. In conclusion, DAL is associated with AKI. Intravenous ANP administration may be one of the promoting factors of DAL, which leads to AKI, indicating a possible novel mechanism of AKI.

Atrial natriuretic peptide protects against bleomycin-induced pulmonary fibrosis via vascular endothelial cells in mice

BackgroundPulmonary fibrosis is a life-threatening disease characterized by progressive dyspnea and worsening pulmonary function. Atrial natriuretic peptide (ANP), a heart-derived secretory peptide used clinically in Japan for the treatment of acute heart failure, exerts a wide range of protective effects on various organs, including the heart, blood vessels, kidneys, and lungs. Its therapeutic properties are characterized by anti-inflammatory and anti-fibrotic activities mediated by the guanylyl cyclase-A (GC-A) receptor. We hypothesized that ANP would have anti-fibrotic and anti-inflammatory effects on bleomycin (BLM)-induced pulmonary fibrosis in mice.MethodsMice were divided into three groups: normal control, BLM with vehicle, and BLM with ANP. ANP (0.5 μg/kg/min via osmotic-pump, subcutaneously) or vehicle administration was started before BLM administration (1 mg/kg) and continued until the mice were sacrificed. At 7 or 21 days after BLM administration, fibrotic changes and infiltration of inflammatory cells in the lungs were assessed based on histological findings and analysis of bronchoalveolar lavage fluid. In addition, fibrosis and inflammation induced by BLM were evaluated in vascular endothelium-specific GC-A overexpressed mice. Finally, attenuation of transforming growth factor-β (TGF-β) signaling by ANP was studied using immortalized mouse endothelial cells stably expressing GC-A receptor.ResultsANP significantly decreased lung fibrotic area and infiltration of inflammatory cells in lungs after BLM administration. Furthermore, similar effects of ANP were observed in vascular endothelium–specific GC-A overexpressed mice. In cultured mouse endothelial cells, ANP reduced phosphorylation of Smad2 after TGF-β stimulation.ConclusionsANP exerts protective effects on BLM-induced pulmonary fibrosis via vascular endothelial cells.

Atrial natriuretic peptide protects against cisplatin-induced granulocytopenia.

Granulocytopenia is the major toxicity associated with cisplatin treatment. Atrial natriuretic peptide (ANP) is a cardiac hormone used clinically for the treatment of acute heart failure in Japan. ANP exerts a wide range of protective effects on various organs, including the heart, blood vessels, lungs, and kidneys. This study's objective was to investigate the protective effects of ANP on cisplatin-induced granulocytopenia in mice. The mice were divided into two groups: cisplatin with vehicle and cisplatin with ANP. ANP (1.5μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started 1day before cisplatin injection until the mice were killed. At 0, 2, 4, 8, and 14days after cisplatin injection (16mg/kg, intraperitoneally as a single dose), the white blood cell, red blood cell, and platelet counts were measured in the peripheral blood in both groups. The numbers of total and live cells and colony-forming unit-granulocyte-macrophage (CFU-GM) colonies in the bone marrow of the mice were also examined. In addition, at 0, 0.5, 1, and 2days after cisplatin injection, serum granulocyte colony-stimulating factor (G-CSF) levels were measured. ANP significantly attenuated the white blood cell count decrease in the peripheral blood 2 and 4days after cisplatin injection. ANP also attenuated the decrease in the number of live cells and CFU-GM colonies in bone marrow 2, 4, and 8days after cisplatin injection. ANP significantly increased serum G-CSF levels 1day after cisplatin injection. ANP has protective effects in cisplatin-induced granulocytopenia, with increased G-CSF production.

The effect of atrial natriuretic peptide infusion on intestinal injury in septic shock.

Background and Aims:The aim of this study is to assess the effect of atrial natriuretic peptide (ANP) on intestinal ischemia-reperfusion injury in septic shock.Material and Methods:A prospective randomized controlled, observer-blinded study was carried out in surgical Intensive Care Unit (ICU), University Hospital. Forty adult patients in septic shock were randomly divided into two groups, control group (Group C) received normal saline and ANP group (Group A) patients received ANP in the form of 1.5 mg vial added to 250 ml solvent in plastic bag (1 ml = 6 micg) given at 2 mcg/kg intravenous bolus over 1 min followed by 0.01 mcg/kg/min for 24 h. The primary outcome measurements were blood marker of intestinal hypoperfusion in form of intestinal fatty acid binding protein (I-FABP), malondialdehyde (MDA), myloperoxidase enzyme activity (MPO), protein carbonyl (PC), and glutathione peroxidase activity (GPA) measured before start of ANP infusion, 6 h, 12 h, and 24 h after start of infusion. The secondary outcome measurements were the duration of noradrenaline infusion, duration of ICU stay, hospital mortality rate, and complications related to ANP.Results:In comparison with Group C, Group A showed a significant decrease (P < 0.05) in serum level of MPO, MDA, PC, and I-FABP, with a significant increase (P < 0.05) in serum level of GPA, 6 h, 12 h, and 24 h after the start of ANP infusion. There was significant decrease (P < 0.05) in mean duration of noradrenaline infusion, the length of ICU stay and mortality rate in Group A in comparison with Group C. In Group A, seven patients had mean arterial blood pressure < 65 mmHg but respond to volume resuscitation, three patients serum sodium was 125–130 mmol/L.Conclusion:In cases of septic shock, concomitant administration of ANP with noradrenaline may have a protective effect against intestinal injury through a decrease in the level of intestinal hypoperfusion owing to its anti-inflammatory and antioxidant effect.