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Background: Atrial natriuretic peptide (ANP) is a cardiovascular and metabolic hormone that has been identified recently as being associated with chronic kidney disease (CKD) without diabetes. Cytokines such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and adiponectin (ADP) contribute to the development of type 2 diabetes (T2DM). The aim here was to investigate the relationships of ANP with cytokine levels and clinical variables in T2DM nephropathy patients., Methods: A total of 81 participants with T2DM were recruited, including 37 patients with normoalbuminuria, 23 patients with microalbuminuria and 21 patients with macroalbuminuria. Serum concentrations of ANP and cytokines were measured using enzyme-linked immunosorbent assay (ELISA) kits. The correlations between ANP and clinical variables were analyzed. Multiple linear regression and logistic regression models were constructed to test the associations between ANP and the severity and presence of albuminuria., Results: The macroalbuminuria patients exhibited higher plasma levels of ANP, TNF-α, IL-6, and ADP; higher serum creatinine (Cr) and blood urea nitrogen (BUN); and longer duration of diabetes mellitus (DM) than the patients with normoalbuminuria and microalbuminuria. Plasma ANP level was significantly associated with TNF-α (r = 0.876, p < 0.001), IL-6 (r = 0.816, p < 0.001) and ADP (r = 0.772, p < 0.001), independent of the duration of DM or the BUN concentration., Conclusion: ANP is higher in type 2 diabetes mellitus nephropathy subjects, especially those who have macroalbuminuria, which is associated with compensatory responses to inflammation., (© 2021. The Author(s).)

Atrial natriuretic peptide (ANP) is an important hormone in cardiovascular biology. It is activated by the protease corin. In pregnancy, ANP and corin promote uterine spiral artery remodeling, but the underlying mechanism remains unknown. Here we report an ANP function in uterine decidualization and TNF-related apoptosis-inducing ligand-dependent (TRAIL-dependent) death in spiral arterial smooth muscle cells (SMCs) and endothelial cells (ECs). In ANP- or corin-deficient mice, uterine decidualization markers and TRAIL expression were decreased, whereas in cultured human endometrial stromal cells (HESCs), ANP increased decidualization and TRAIL expression. In uterine spiral arteries from pregnant wild-type mice, SMC and EC loss occurred sequentially before trophoblast invasion. In culture, TRAIL from decidualized HESCs induced apoptosis in uterine SMCs, but not in ECs with low TRAIL receptor expression. Subsequently, cyclophilin B was identified from apoptotic SMCs that upregulated endothelial TRAIL receptor and caused apoptosis in ECs. These results indicate that ANP promotes decidualization and TRAIL expression in endometrial stromal cells, contributing to sequential events in remodeling of spiral arteries, including SMC death and cyclophilin B release, which in turn induces TRAIL receptor expression and apoptosis in ECs.

Introduction: Atrial natriuretic peptide (ANP), composed by 28 amino-acids, is well known to modulate fluid and electrolyte homeostasis, the hypothalamic-pituitary-adrenal (HPA) axis activity and the immune system. Since ANP is produced in both heart and in the central nervous system (CNS), in the last years, increasing attention has been devoted to its possible role in neuropsychiatric disorders. Indeed, scattered data would indicate its possible role in anxiety, major depression, addictive behaviors, post-traumatic stress disorder and other stress-related disorders. Further, ANP has been hypothesized to represent one of the factors linking depression to cardiovascular health and the immune system., Aims: Given the paucity of available information, the aim of this paper was to review the current literature on the role of ANP in the CNS and in the pathophysiology of different neuropsychiatric and stress-related conditions., Discussion: Supporting data on ANP in psychiatric disorders are still limited to animal studies, or to a few "real" findings in patients gathered some decades ago that should be replicated in larger clinical samples., Conclusion: Further studies are necessary to understand the possible implications of ANP in neuropsychiatry, because potentially it might represent a new way for innovative psychopharmacological treatments in different conditions, all underlaid by hyperactive HPA axis., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Investigations into the mixed muscle-secretory phenotype of cardiomyocytes from the atrial appendages of the heart led to the discovery that these cells produce, in a regulated manner, two polypeptide hormones - the natriuretic peptides - referred to as atrial natriuretic factor or atrial natriuretic peptide (ANP) and brain or B-type natriuretic peptide (BNP), thereby demonstrating an endocrine function for the heart. Studies on the gene encoding ANP (NPPA) initiated the field of modern research into gene regulation in the cardiovascular system. Additionally, ANP and BNP were found to be the natural ligands for cell membrane-bound guanylyl cyclase receptors that mediate the effects of natriuretic peptides through the generation of intracellular cGMP, which interacts with specific enzymes and ion channels. Natriuretic peptides have many physiological actions and participate in numerous pathophysiological processes. Important clinical entities associated with natriuretic peptide research include heart failure, obesity and systemic hypertension. Plasma levels of natriuretic peptides have proven to be powerful diagnostic and prognostic biomarkers of heart disease. Development of pharmacological agents that are based on natriuretic peptides is an area of active research, with vast potential benefits for the treatment of cardiovascular disease.

The spiral ganglion neurons (SGNs) are the primary afferent neurons in the spiral ganglion (SG), while their degeneration or loss would cause sensorineural hearing loss. As a cardiac-derived hormone, atrial natriuretic peptide (ANP) plays a critical role in cardiovascular homeostasis through binding to its functional receptors (NPR-A and NPR-C). ANP and its receptors are widely expressed in the mammalian nervous system where they could be implicated in the regulation of multiple neural functions. Although previous studies have provided direct evidence for the presence of ANP and its functional receptors in the inner ear, their presence within the cochlear SG and their regulatory roles during auditory neurotransmission and development remain largely unknown. Based on our previous findings, we investigated the expression patterns of ANP and its receptors in the cochlear SG and dissociated SGNs and determined the influence of ANP on neurite outgrowth in vitro by using organotypic SG explants and dissociated SGN cultures from postnatal rats. We have demonstrated that ANP and its receptors are expressed in neurons within the cochlear SG of postnatal rat, while ANP may promote neurite outgrowth of SGNs via the NPR-A/cGMP/PKG pathway in a dose-dependent manner. These results indicate that ANP would play a role in normal neuritogenesis of SGN during cochlear development and represents a potential therapeutic candidate to enhance regeneration and regrowth of SGN neurites., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Fei Sun et al.)

Atrial natriuretic peptide (ANP) exerts anxiolytic effects in animals and humans. Patients with anxiety, trauma-associated and depressive disorders exhibit lower ANP plasma levels compared to healthy individuals. However, the role of ANP in patients with major depressive disorder (MDD) with and without concomitant adverse childhood experiences (ACE) and in healthy individuals with and without ACE is not clear. We recruited a total of 93 women: 23 women with MDD and ACE, 24 women with MDD without ACE, 22 women with ACE but no current or lifetime MDD, and 24 healthy women without ACE. ANP plasma levels were measured with a radioimmunoassay. The four groups did not differ in demographic and clinical variables. We found a positive correlation between age and plasma levels of ANP (r = .39; p <  .001). After controlling for age, there was no significant main effect of MDD or ACE on ANP plasma levels, but a significant interaction between MDD and ACE such that ACE was associated with reduced basal ANP levels in the absence of MDD. We assume that low plasma ANP might be a consequence of ACE in the absence of current psychopathology. Therefore, future studies are needed to replicate our findings and to characterize the influencing factors of ACE on ANP more comprehensively, for example by including a comprehensive trauma and comorbidity anamnesis as well as cardiovascular state and risk factors., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The Atrial Natriuretic Peptide (ANP) is a hormone secreted by the heart, and, due to its mechanisms in the central nervous system, it is credited with a possible anxiolytic and stress-reducing effect. The aim of this study consisted of examining the values of ANP in adults and its relationship with anxiety and depression. An exploratory, observational and cross-sectional study was adopted. The sample was composed by 30 attending a Mental Health Service. The Beck Anxiety Inventory and the Beck Depression Inventory were applied, and a negative association between ANP values and the depressive state under Beck scale (p=0.017) was observed, more precisely lower ANP levels in patients with Beck's severe depression state. There were no relevant associations between ANP values and Beck's anxiety states. In order to reinforce this research topic, it is necessary to perform longitudinal studies, gather wider samples and include biological indicators for anxiety and depression as alpha-amylase and cortisol.

Midregional pro-atrial natriuretic peptide (MR-proANP), first isolated in 1981, is a novel peptide with multiple biological functions, especially within the cardiovascular system. This peptide plays an important role in many processes, including natriuresis, diuresis, and other physiological and pathophysiological pathways in the human body. Several electronic databases (PubMed, EBSCO, Scopus, and ScienceDirect) were analyzed in the present literature review. The aim of this study was to elucidate the wide roles of MR-proANP, which can be analyzed because of the development of a new sandwich immunoassay, and to determine the possible diagnostic and prognostic implications of MR-proANP on cardiovascular disease and other disorders. The studies discussed in this literature review provide valuable data on the role of ANP in the pathogenesis, diagnostic process, prognosis, and potential therapeutic strategies for disease. Although ANP is mainly associated with cardiovascular disease, it may be used as a biomarker in diabetology, neurology, and metabolic disorders.

Natriuretic peptides are a group of hormones including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C type (CNP), urodilatin and guanilyn. ANP (half-life: 2-4 min), is secreted by the atrium, BNP (half-life: 20 min) by the ventricle, CNP by the vascular endothelium, urodilatin by the kidney and guanylin by the intestine. These natriuretic peptides prevent water and salt retention through renal action, vasodilatation and hormonal inhibition of aldosterone, vasopressin and cortisol. These peptides also have a recently demonstrated metabolic effect through an increase of lipolysis, thermogenesis, beta cell proliferation and muscular sensitivity to insulin. Blood levels of these natriuretic peptides depend on "active NPR-A receptors/clearance NPR-C receptors", the last ones being abundant on adipocytes. Therefore, natriuretic peptides act as adipose tissue regulator and constitute a link between blood pressure and metabolic syndrome. They are used as markers and treatment of cardiac failure. Other applications are on going. BNP and NT-proBNP (inactive portion de la pro-hormone) are used as markers of cardiac failure since they have a longer half-life than ANP. BNP decrease is quicker and more important than that one of NT-ProBNP in case of improvement of cardiac failure. Chronic renal insufficiency and beta-blockers increase BNP levels. BNP measurement is useless under treatment with neprilysine inhibitors such as sacubitril, one of the neutral endopeptidases involved in catabolism of natriuretic peptides. The association sacubitril/valsartan is a new treatment of chronic cardiac failure, acting through the decrease of ANP catabolism., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Aims: Erythropoiesis is a tightly controlled biological event, but its regulation under non-hypoxic conditions, however, remains unresolved. We examined whether acute changes in central venous blood pressure (CVP) elicited by whole-body tilting affect erythropoietin (EPO) concentration according to volume-regulating hormones., Methods: Plasma EPO, angiotensin II (ANGII), aldosterone, pro-atrial natriuretic peptide (proANP) and copeptin concentrations were measured at supine rest and up to 3 h during 30° head-up (HUT) and head-down tilt (HDT) in ten healthy male volunteers. Plasma albumin concentration was used to correct for changes in plasma volume and CVP was estimated through the internal jugular vein (IJV) aspect ratio with ultrasonography., Results: From supine rest, the IJV aspect ratio was decreased and increased throughout HUT and HDT respectively. Plasma EPO concentration increased during HUT (13%; P = 0.001, P for linear component = 0.017), independent of changes in albumin concentration. Moreover, ANGII and copeptin concentrations increased during HUT, while proANP decreased. The increase in EPO concentration during HUT disappeared when adjusted for changes in copeptin. During HDT, EPO, ANGII and copeptin concentrations remained unaffected while proANP increased. In regression analyses, EPO was positively associated with copeptin (β = 0.55; 95% CI = 0.18, 0.93; P = 0.004) irrespective of changes in other hormones and albumin concentration., Conclusion: Reduction in CVP prompts an increase in plasma EPO concentration independent of hemoconcentration and hence suggests CVP per se as an acute regulator of EPO synthesis. This effect may be explained by changes in volume-regulating hormones., (© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Atrial natriuretic peptide dose-dependently inhibited spontaneous phase and tonic activity of smooth muscle strips from the capsule of isolated bovine mesenteric lymph nodes. Pretreatment with L-NAME, diclofenac, and methylene blue had practically no effect on the peptide-induced relaxation responses. In contrast, glibenclamide significantly reduced the inhibitory effect of atrial natriuretic peptide. We suppose that the NO-dependent and cyclooxygenase signaling pathways are not involved in implementation of the inhibitory effects of atrial natriuretic peptide. ATP-sensitive K(+)-channels of the smooth muscle cell membrane are the last component in the signaling pathway leading to relaxation of smooth muscles of the lymph node capsule caused by atrial natriuretic peptide; activation of these channels leads to membrane hyperpolarization and smooth muscle relaxation.

Hyponatremia is one of the most common electrolyte imbalances in HIV patients. The differential diagnosis may include hypovolemic hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), and adrenal insufficiency. Here, we describe a case of hyponatremia secondary to cerebral salt wasting syndrome (CSWS) in an HIV patient with cryptococcal meningitis. A 52-year-old man with a history of diabetes and HIV was admitted for headache and found to have cryptococcal meningitis. He was also found to have asymptomatic hyponatremia. He had signs of hypovolemia, such as orthostatic hypotension, dry mucosa, decreased skin turgor, hemoconcentration, contraction alkalosis, and high BUN/Cr ratio. The laboratory findings revealed sodium of 125 mmol/L, potassium of 5.5 mmol/L, urine osmolality of 522 mOsm/kg, urine sodium of 162 mmol/L, and urine chloride of 162 mmol/L. We started normal saline for hypovolemia, each 1 L prior and after amphotericin therapy. However, hypovolemia did not improve significantly despite IV fluid. Cosyntropin stimulation test was negative, and renin level was 0.25 ng·mL·h, with the aldosterone level of <1 ng/dL, the serum brain natriuretic peptide of 15 pg/mL, and serum uric acid of 2.8 mg/dL. The diagnosis of CSWS was suspected, fludrocortisone was tried, and hypovolemia and hyponatremia improved. Cryptococcal meningitis in HIV patients can present with CSWS, and the distinction between CSWS and SIADH is important because the treatment for CSWS is different than that of SIADH. Both share a similar clinical picture except that CSWS presents with constant hypovolemia despite volume replacement. Salt tablets, normal saline, or fludrocortisone can be used for treatment.

To better understand human adaptation to stress, and in particular to hypoxia, we took advantage of one of nature's experiments at high altitude (HA) and studied Ethiopians, a population that is well-adapted to HA hypoxic stress. Using whole-genome sequencing, we discovered that EDNRB (Endothelin receptor type B) is a candidate gene involved in HA adaptation. To test whether EDNRB plays a critical role in hypoxia tolerance and adaptation, we generated EdnrB knockout mice and found that when EdnrB (-/+) heterozygote mice are treated with lower levels of oxygen (O2), they tolerate various levels of hypoxia (even extreme hypoxia, e.g., 5% O2) very well. For example, they maintain ejection fraction, cardiac contractility, and cardiac output in severe hypoxia. Furthermore, O2 delivery to vital organs was significantly higher and blood lactate was lower in EdnrB (-/+) compared with wild type in hypoxia. Tissue hypoxia in brain, heart, and kidney was lower in EdnrB (-/+) mice as well. These data demonstrate that a lower level of EDNRB significantly improves cardiac performance and tissue perfusion under various levels of hypoxia. Transcriptomic profiling of left ventricles revealed three specific genes [natriuretic peptide type A (Nppa), sarcolipin (Sln), and myosin light polypeptide 4 (Myl4)] that were oppositely expressed (q < 0.05) between EdnrB (-/+) and wild type. Functions related to these gene networks were consistent with a better cardiac contractility and performance. We conclude that EDNRB plays a key role in hypoxia tolerance and that a lower level of EDNRB contributes, at least in part, to HA adaptation in humans.

The balance between vasoconstrictor/sodium-retaining and vasodilator/natriuretic systems is essential for maintaining body fluid and electrolyte homeostasis. Natriuretic peptides, such as atrial natriuretic peptide (ANP), belong to the vasodilator/natriuretic system. ANP is produced by the conversion of pro-ANP into ANP, which is achieved by a proteolytical cleavage executed by corin. In the kidney, ANP binds to the natriuretic peptide receptor-A (NPR-A) and enhances its guanylyl cyclase activity, thereby increasing intracellular cyclic guanosine monophosphate production to promote natriuretic and renoprotective responses. In the glomerulus, ANP increases glomerular permeability and filtration rate and antagonizes the deleterious effects of the renin-angiotensin-aldosterone system activation. Along the nephron, natriuretic and diuretic actions of ANP are mediated by inhibiting the basolaterally expressed Na(+)-K(+)-ATPase, reducing apical sodium, potassium, and protein organic cation transporter in the proximal tubule, and decreasing Na(+)-K(+)-2Cl(-) cotransporter activity and renal concentration efficiency in the thick ascending limb. In the medullary collecting duct, ANP reduces sodium reabsorption by inhibiting the cyclic nucleotide-gated cation channels, the epithelial sodium channel, and the heteromeric channel transient receptor potential-vanilloid 4 and -polycystin 2 and diminishes vasopressin-induced water reabsorption. Long-term ANP treatment may lead to NPR-A desensitization and ANP resistance, resulting in augmented sodium and water reabsorption. In mice, corin deficiency impairs sodium excretion and causes salt-sensitive hypertension. Characteristics of ANP resistance and corin deficiency are also encountered in patients with edema-associated diseases, highlighting the importance of ANP signaling in salt-water balance and renal pathophysiology., (Copyright © 2015 the American Physiological Society.)

Non-modulating hypertension (NMHT) is a high renin subtype of salt sensitive hypertension, which fails to achieve renal vasodilatation and a correct Na(+) handling during sodium load. We investigate, in MHT and NMHT, the role of ANP, the renin-angiotensin system and PgI2, in the renal sodium handling mechanisms. After 10 days of low (20mmol.L) or after 72hs of high (250mmol.L) sodium intake, 13 NMHT (34±5y; 9 male) and 13 MHT (32±4y; 10male) were studied. Pro-ANP (1-30) PgI2, PRA and total exchangeable Na(+)24 (ENa(+)) were measured. Under low sodium intake, PRA (4.2±0.5ng.ml.h; p<0.05) and Pro-ANP (78.6±2pg/ml, p<0.05) were higher than in NMHT under (3.1±0.4ng.ml.h and 69.8±3 pg/ml). After 72h of high Na(+) intake, Pro-ANP (1-30) increased significantly only in MHT (82.1±3pg/ml, p<0.05). PgI2, under low sodium intake (1.83±0.2pg/24h), increased in MHT after 72h under high sodium (2.58±0.5pg/ 24h, p<0.02). Under low sodium diet, PgI2 (2.16±0.11pg/24h) was as higher in NMHT, as in MHT. After 72h under high Na+ intake, it failed to show any change (2.61±0.36 pg/24h; p=ns). A significant correlation between variations in ENa(+) and mean blood pressure (r=0.50, p<0.01), variations in Pro-ANP (1-30) values and ENa(+) in MHT (r=0.95; p<0.001) while a negative correlation between ENa(+) variations and ENa(+) (r=0.81, p<0.05) was observed in NMHT. ENa(+) variations were only significantly related to variations in FF in MHT. Thus, in NMHT, there is an unbalanced relationship between vasonstrictor and vasodilator mediators. From these, as an extrarenal homeostatic mediator, ANP seems to play an important role to compensate the altered renal sodium handling.

Apart from control of circulating fluid, atrial natriuretic peptide (ANP) exhibits anti-inflammatory effects in the lung. However, molecular mechanisms of ANP anti-inflammatory effects are not well-understood. Peripheral microtubule (MT) dynamics is essential for agonist-induced regulation of vascular endothelial permeability. Here we studied the role of MT-dependent signaling in ANP protective effects against endothelial cell (EC) barrier dysfunction and acute lung injury induced by Staphylococcus aureus-derived peptidoglican-G (PepG). PepG-induced vascular endothelial dysfunction was accompanied by MT destabilization and disruption of MT network. ANP attenuated PepG-induced MT disassembly, NFκB signaling and activity of MT-associated Rho activator GEF-H1 leading to attenuation of EC inflammatory activation reflected by expression of adhesion molecules ICAM1 and VCAM1. ANP-induced EC barrier preservation and MT stabilization were linked to phosphorylation and inactivation of MT-depolymerizing protein stathmin. Expression of stathmin phosphorylation-deficient mutant abolished ANP protective effects against PepG-induced inflammation and EC permeability. In contrast, siRNA-mediated stathmin knockdown prevented PepG-induced peripheral MT disassembly and endothelial barrier dysfunction. ANP protective effects in a murine model of PepG-induced lung injury were associated with increased phosphorylation of stathmin, while exacerbated lung injury in the ANP knockout mice was accompanied by decreased pool of stable MT. Stathmin knockdown in vivo reversed exacerbation of lung injury in the ANP knockout mice. These results show a novel MT-mediated mechanism of endothelial barrier protection by ANP in pulmonary EC and animal model of PepG-induced lung injury via stathmin-dependent control of MT assembly., (Copyright © 2014 Elsevier B.V. All rights reserved.)

We recently observed in human umbilical artery smooth muscle cells that testosterone activates protein kinase G and stimulates large-conductance Ca²⁺ activated (BKCa) and voltage sensitive (KV) potassium channels. In the same work, we also show that atrial natriuretic peptide (ANP), an activator of particulate guanylate cyclase (pGC), stimulates the activity of BKCa and KV channels because of protein kinase G activation. The aim of this work was to prove that the relaxant effects of testosterone are also because of the increase of cGMP because of activation of the pGC. Subsarcolemmal cGMP signals were monitored in single cells by recording the cGMP-gated current (ICNG) in human umbilical artery smooth muscle cells expressing the wild-type rat olfactory cyclic nucleotide-gated (CNG) channel. Sodium nitroprusside (10 and 100 μM), ANP (0.1 and 1 μM), or testosterone (0.1, 1, and 10 μM) induced activation of ICNG. This activation induced by testosterone and ANP is bigger than that elicited by sodium nitroprusside. In summary, our study reveals that testosterone and ANP activate the pGC and induce vasorelaxation of human umbilical artery.

Aims: Ursolic acid has recently been reported to increase both atrial natriuretic peptide (ANP) secretion and mechanical dynamics in rabbit atria., Main Methods: The present study was designed to clarify the regulatory effects of ursolic acid on the β-adrenergic or muscarinic receptor-mediated changes in ANP secretory and contractile function allowing measurement of atrial dynamics such as pulse pressure, stroke volume, and cAMP efflux in isolated perfused beating rabbit atria., Key Findings: Pretreatment with ursolic acid significantly attenuated the isoproterenol (β-adrenergic agonist)-induced decrease in ANP secretion and increases in cAMP levels and atrial dynamics. Interestingly, ursolic acid concentration-dependently accentuated the acetylcholine-induced increase in ANP secretion and decrease in pulse pressure in the presence of isoproterenol (p<0.001). These findings indicate that acetylcholine-induced increase in ANP secretion is potentiated by ursolic acid; furthermore, acetylcholine-induced decrease in atrial dynamics is also potentiated by ursolic acid, suggesting that ursolic acid regulates muscarinic receptor-mediated secretory and contractile responses in perfused beating rabbit atria., Significance: This implicates for the beneficial effects of ursolic acid in the regulation of cardiovascular and body fluid homeostasis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The natriuretic peptide (NP) family includes atrial (ANP), brain or B-type (BNP) and C-type NP (CNP). A huge number of experimental and clinical studies, published in the 1st decade of this century, have added further support to the hypothesis that endocrine function in the human heart is a relevant component of a complex network including endocrine, nervous and immune systems. The NP hormones constitute a well-integrated regulatory system and share a similar spectrum of biological actions, although there are some differences in biological potency between ANP, BNP and CNP. However, several important issues on this field need to be investigated further. The production, secretion and peripheral degradation pathways of both BNP and CNP should be clarified in detail. In particular, the hypothesis that the circulating plasma pool of the prohormone can function as a precursor of the active peptide hormone should be demonstrated definitively. Recent findings indicate that peripheral processing of circulating prohormones could likely be submitted to regulatory rules, which might be impaired in patients with heart failure, opening up new perspectives even in the treatment of heart failure. This hypothesis suggests a novel pharmacological target for drugs inducing and/or modulating the maturation of the prohormone into active hormone., (© 2014 S. Karger AG, Basel.)

Studies of left atrial (LA) function, until the latter part of the 20th century, were mostly limited to experimental animal models and to studies related to clinical research in the cardiac catheterization laboratory. For this reason, LA function has received considerably less attention than left ventricular (LV) functions, even though evidence suggests that LA myopathy and failure may exist as an isolated entity, precede and/or coexist with LV myopathy. The introduction of echocardiography and Doppler echocardiography in clinical practice has contributed significantly to our understanding of LA function and its interrelationships with the LV, aorta, pulmonary artery and other parts of the cardiovascular system. In addition, LA with the secretion of atrial natriuretic peptides is playing an important role in cardiovascular and neurohumoral homeostasis. Today, it is well known that LA structural and functional abnormalities that are present in many diseases and disorders constitute a powerful prognostic indicator. As technology (echocardiography, magnetic resonance imaging, computed tomography and others) continues to evolve, it is expected that, in the near future, LA structure and function will be routinely used as LV function is used today., (© 2014 S. Karger AG, Basel.)

Background: Sodium and water transport across renal proximal tubules is regulated by diverse hormones such as dopamine and urodilatin. We have previously reported that urodilatin stimulates extraneuronal dopamine uptake in external renal cortex by activation of the type A natriuretic peptide receptor, coupled to cyclic guanylate monophosphate signaling and protein kinase G. Moreover, urodilatin enhances dopamine-induced inhibition of Na+, K+-ATPase activity in renal tubules. The aim of the present study was to evaluate whether urodilatin could also alter renal dopamine synthesis, release, catabolism and turnover., Methods: The effects of urodilatin on dopamine synthesis, release, catabolism and turnover were measured in samples of renal cortex from Sprague Dawley rats., Results: The results indicate that urodilatin increases L-DOPA decarboxylase activity and decreases catechol-o-methyl transferase and monoamine oxidase activity. Moreover, urodilatin does not affect either dopamine basal secretion or potassium chloride-induced dopamine release in external renal cortex, and reduces amine turnover., Conclusions: Both the present results and previous findings show that urodilatin modifies dopamine metabolism in external renal cortex of rats by enhancing dopamine uptake and synthesis and by decreasing catechol-o-methyl transferase and monoamine oxidase activity and dopamine turnover. Those effects taken together may favor dopamine accumulation in renal cells and increase its endogenous content and availability. This would permit D1 receptor recruitment and stimulation and, in turn, overinhibition of Na+, K+-ATPase activity, which results in decreased sodium reabsorption. Therefore, urodilatin and dopamine enhance natriuresis and diuresis through a common pathway.

Atrial natriuretic peptide (ANP) plays a pivotal role in modulation of vascular function and it is also involved in the pathophysiology of several cardiovascular diseases. We provide an updated overview of the current appraisal of ANP vascular effects in both animal models and humans. We describe the physiological implications of ANP vasomodulatory properties as well as the involvement of ANP, through its control of vascular function, in hypertension and heart failure. The principal molecular mechanisms underlying regulation of vascular tone, that is natriuretic peptide receptor type A/cyclic guanylate monophosphate, natriuretic peptide receptor type C, nitric oxide system, are discussed. We review the literature on therapeutic implications of ANP in hypertension and heart failure, examining the potential use of ANP analogues, neutral endopeptidase (NEP) inhibitors, ACE/NEP inhibitors, angiotensin receptor blocker (ARB)/NEP inhibitors, the new dual endothelin-converting enzyme (ECE)/NEP inhibitors and ANP-based gene therapy. The data discussed support the role of ANP in different pathological conditions through its vasomodulatory properties. They also indicate that ANP may represent an optimal therapeutic agent in cardiovascular diseases.

Cardiac hormone atrial natriuretic peptide (ANP) and its receptor natriuretic peptide receptor-A (NPR-A) system acts as an intrinsic negative regulator of abnormal extracellular matrix (ECM) remodeling in the heart. However, the underlying mechanism by which ANP/NPR-A system opposes the ECM remodeling in the diseased heart is not well understood. Here, we investigated the anti-fibrotic mechanism of ANP/NPR-A in fibrotic agonist Angiotensin- II (ANG II)-treated adult cardiac fibroblast (CF) cells. Normal and NPR-A-suppressed adult CF cells were treated with ANG II (10(-7) M) in the presence and absence of ANP (10(-8) M) for 24 h. Total collagen concentration, activity and expression of MMP-2 and MMP-9, and nuclear translocation of Nuclear factor-kappaB (NF-κB-p50) were studied. NPR-A-suppressed adult CF cells exhibited a more pronounced increase in collagen production, ROS generation, and NF-κB-p50 nuclear translocation as compared to adult CF cells treated with agonist alone. ANP co-treatment significantly reverses the agonist-induced above changes in normal adult CF cells, while it failed to reverse the agonist-induced collagen synthesis in the NPR-A-suppressed adult CF cells. The cGMP analog (8-bromo-cGMP) treatment significantly attenuated the agonist-induced collagen synthesis both in normal and NPR-A-suppressed adult cells. The results of this study suggest that ANP/NPR-A signaling system antagonizes the agonist-induced collagen synthesis via suppressing the activities of MMP-2, MMP-9, ROS generation, and NF-κB nuclear translocation mechanism.

Rationale: C2238 atrial natriuretic peptide (ANP) minor allele (substitution of thymidine with cytosine in position 2238) associates with increased risk of cardiovascular events., Objective: We investigated the mechanisms underlying the vascular effects of C2238-αANP., Methods and Results: In vitro, human umbilical vein endothelial cell were exposed to either wild-type (T2238)- or mutant (C2238)-αANP. Cell survival and apoptosis were tested by Trypan blue, annexin V, and cleaved caspase-3 assays. C2238-αANP significantly reduced human umbilical vein endothelial cell survival and increased apoptosis. In addition, C2238-αANP reduced endothelial tube formation, as assessed by matrigel. C2238-αANP did not differentially modulate natriuretic peptide receptor (NPR)-A/B activity with respect to T2238-αANP, as evaluated by intracellular cGMP levels. In contrast, C2238-αANP, but not T2238-αANP, markedly reduced intracellular cAMP levels in an NPR-C-dependent manner. Accordingly, C2238-αANP showed higher affinity binding to NPR-C, than T2238-αANP. Either NPR-C inhibition by antisense oligonucleotide or NPR-C gene silencing by small interfering RNA rescued survival and tube formation of human umbilical vein endothelial cell exposed to C2238-αANP. Similar data were obtained in human aortic endothelial cell with NPR-C knockdown. NPR-C activation by C2238-αANP inhibited the protein kinase A/Akt1 pathway and increased reactive oxygen species. Adenovirus-mediated Akt1 reactivation rescued the detrimental effects of C2238-αANP. Overall, these data indicate that C2238-αANP affects endothelial cell integrity through NPR-C-dependent inhibition of the cAMP/protein kinase A/Akt1 pathway and increased reactive oxygen species production. Accordingly, C2238-αANP caused impairment of acetylcholine-dependent vasorelaxation ex vivo, which was rescued by NPR-C pharmacological inhibition. Finally, subjects carrying C2238 minor allele showed early endothelial dysfunction, which highlights the clinical relevance of our results., Conclusions: C2238-αANP reduces endothelial cell survival and impairs endothelial function through NPR-C signaling. NPR-C targeting represents a potential strategy to reduce cardiovascular risk in C2238 minor-allele carriers.

Epithelial sodium channels (ENaCs) located at the apical membrane of polarized epithelial cells are regulated by the second messenger guanosine 3',5'-cyclic monophosphate (cGMP). The mechanism for this regulation has not been completely characterized. Guanylyl cyclases synthesize cGMP in response to various intracellular and extracellular signals. We investigated the regulation of ENaC activity by natriuretic peptide-dependent activation of guanylyl cyclases in Xenopus 2F3 cells. Confocal microscopy studies show natriuretic peptide receptors (NPRs), including those coupled to guanylyl cyclases, are expressed at the apical membrane of 2F3 cells. Single-channel patch-clamp studies using 2F3 cells revealed that atrial natriuretic peptide (ANP) or 8-(4-chlorophenylthio)-cGMP, but not C-type natriuretic peptide or cANP, decreased the open probability of ENaC. This suggests that NPR-A, but not NPR-B or NPR-C, is involved in the natriuretic peptide-mediated regulation of ENaC activity. Also, it is likely that a signaling pathway involving cGMP and nitric oxide (NO) are involved in this mechanism, since inhibitors of soluble guanylyl cyclase, protein kinase G, inducible NO synthase, or an NO scavenger blocked or reduced the effect of ANP on ENaC activity.

In pregnancy, uterine spiral artery remodeling is an adaptive morphological change at the maternal and fetal interface, which is critical for dilating the artery and promoting blood flow to the fetus. Incompletely remodeled spiral arteries have been recognized as a common pathological feature in preeclamptic patients. To date, the molecular mechanism that controls spiral artery remodeling is not well defined. Corin is a transmembrane serine protease discovered in the heart, where it converts pro-atrial natriuretic peptide (pro-ANP) to active ANP, a cardiac hormone that regulates salt-water balance and blood pressure. Recent studies show that corin is up-regulated in the decidua of the pregnant uterus, suggesting a potential role of corin in pregnancy. In mice lacking corin or ANP, high blood pressure and proteinuria were found at late gestational stages. Histological analysis indicated delayed trophoblast invasion and impaired spiral artery remodeling in the uterus. In humans, CORIN gene mutations were identified in patients with preeclampsia. In this review, we discuss the function of corin and ANP in regulating blood pressure and their potential role in preeclampsia., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP-dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training-induced improvement in skeletal muscle fat oxidative capacity in humans.

Background: Marinobufagenin (MBG) promotes natriuresis via inhibition of renotubular Na/K-ATPase (NKA) and causes vasoconstriction via inhibition of vascular NKA. Atrial natriuretic peptide (ANP), via cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-dependent mechanism, sensitizes renal NKA to MBG but reduces MBG-induced inhibition of vascular NKA. As aging is associated with a downregulation of cGMP/PKG signaling, we hypothesized that in older rats, ANP would not potentiate renal effects of MBG and would not oppose vascular effects of MBG., Methods: In younger (3-month-old) and older (12-month-old) Sprague-Dawley rats, we compared SBP, natriuresis, activity of NKA in aorta and renal medulla, and levels of MBG and α-ANP at baseline and following acute NaCl loading (20%, 2.5 ml/kg, intraperitoneally), and studied modulation of MBG-induced NKA inhibition by α-ANP in vitro., Results: As compared with younger rats, NaCl-loaded older rats exhibited a greater MBG response, greater SBP elevation (25 vs. 10 mmHg, P < 0.01) and greater inhibition of NKA in aorta (39 vs. 7%, P < 0.01), 30% less natriuresis, and less inhibition of renal NKA (25 vs. 42%, P < 0.05) in the presence of comparable responses of α-ANP and cGMP. In aorta and kidney of older rats, the levels of PKG were reduced, the levels of phosphodiesterase-5 were increased compared with that in young rats, and α-ANP failed to modulate MBG-induced NKA inhibition., Conclusion: Age-associated downregulation of cGMP/PKG-dependent signaling impairs the ability of ANP to modulate the effects of MBG on the sodium pump, which contributes to salt sensitivity.

Twin-twin transfusion syndrome (TTTS) is a serious condition that affects 10% to 15% of twin pregnancies with monochorionic diamniotic placentation. The pathophysiology of TTTS is not completely understood; however, the presence of unbalanced placental vascular communications within a shared circulation has been implicated in its development. The presentation of TTTS is highly variable, and it does not always progress in a predictable manner. Monochorionic twin gestations should, therefore, be monitored for signs of TTTS with serial sonograms starting in the second trimester. Early TTTS can be managed conservatively. However, without intervention, early-onset advanced TTTS is associated with a high perinatal loss rate and risk of severe neurologic impairment among survivors. Limited studies suggest that fetoscopic laser photocoagulation is the best available treatment for advanced TTTS diagnosed in the second trimester. Even with laser therapy, there remains a significant risk of twin demise and neurologic handicap in survivors., (Copyright © 2012. Published by Elsevier Inc.)

Objectives: The aim of this study was to investigate the impact of rs5065 atrial natriuretic peptide (ANP) gene variant on coronary artery disease (CAD) and its outcomes and to gain potential mechanistic insights on the association with CAD., Background: Either modified ANP plasma levels or peptide structural alterations have been involved in development of cardiovascular events., Methods: Three hundred ninety-three control subjects and 1,004 patients undergoing coronary angiography for suspected CAD (432 stable angina [SA], 572 acute coronary syndrome [ACS]) were genotyped for rs5065 ANP gene variant. Data in SA and ACS groups were replicated in an independent population of 482 stable angina patients (rSA) and of 675 ACS patients, respectively. Clinical follow-up was available for both SA and rSA patients. Plasma N-terminal-proANP, myeloperoxidase, lipoprotein-associated phospholipase A2, and oxidized low-density lipoprotein were assessed in a subgroup of rSA patients., Results: rs5065 minor allele (MA) was an independent predictor of ACS (odds ratio: 1.90; 95% confidence interval: 1.40 to 2.58, p < 0.001). At follow-up, rs5065 MA was independently associated with a significantly higher rate of major adverse cardiovascular events in the SA group, p < 0.001. Data were replicated in the rSA group at follow-up (p = 0.008). Cox proportional hazard analysis tested by 4 models confirmed higher major adverse cardiovascular events risk in rs5065 MA carriers in both SA and rSA cohorts. Significantly higher myeloperoxidase levels were detected in rs5065 MA carriers (n = 597 [345 to 832 μg/l] vs. n = 488 [353 to 612 μg/l], p = 0.038). No association of rs5065 was observed with N-terminal-proANP levels., Conclusions: The MA of rs5065 ANP gene variant associates with increased susceptibility to ACS and has unfavorable prognostic value in CAD., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro- and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the actions of NPs on endothelial permeability and regeneration., (© 2012 The Author. British Journal of Pharmacology © 2012 The British Pharmacological Society.)

Two classes of guanylyl cyclases (GC) form intracellular cGMP. One is a receptor for atrial natriuretic peptide (ANP) and the other for nitric oxide (NO). The ANP receptor guanylyl cyclase (GC-A) is a membrane-bound, single subunit protein. Nitric oxide activated or soluble guanylyl cyclases (NOGC) are heme-containing heterodimers. These have been shown to be important in cGMP mediated regulation of arterial vascular resistance and renal sodium transport. Recent studies have shown that cGMP produced by both GCs is compartmentalized in the heart and vascular smooth muscle cells. To date, however, how intracellular cGMP generated by ANP and NO is compartmentalized and how it triggers specific downstream targets in kidney cells has not been investigated. Our studies show that intracellular cGMP formed by NO is targeted to cytosolic and cytoskeletal compartments whereas cGMP formed by ANP is restricted to nuclear and membrane compartments. We used two dimensional difference in gel electrophoresis and MALDI-TOF/TOF to identify distinct sub-cellular targets that are specific to ANP and NO signaling in HK-2 cells. A nucleocytoplasmic shuttling protein, heterogeneous nuclear ribonucleo protein A1 (hnRNP A1) is preferentially phosphorylated by ANP/cGMP/cGK signaling. ANP stimulation of HK-2 cells leads to increased cGK activity in the nucleus and translocation of cGK and hnRNP A1 to the nucleus. Phosphodiestaerase-5 (PDE-5 inhibitor) sildenafil augmented ANP-mediated effects on hnRNPA1 phosphorylation, translocation to nucleus and nuclear cGK activity. Our results suggest that cGMP generated by ANP and SNAP is differentially compartmentalized, localized but not global changes in cGMP, perhaps at different sub-cellular fractions of the cell, may more closely correlate with their effects by preferential phosphorylation of cellular targets., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Traditionally associated with female reproduction, oxytocin (OT) was revisited recently and was revealed to have several new roles in the cardiovascular system. Functional OT receptors have been discovered in the rat and human heart, as well as in vascular beds. The cardiovascular activities of OT include: (i) lowering blood pressure; (ii) negative cardiac inotropy and chronotropy; (iii) parasympathetic neuromodulation; (iv) vasodilatation; (v) anti-inflammatory; (vi) antioxidative; and (vii) metabolic effects. These outcomes are mediated, at least in part, by stimulating cardioprotective mediators, such as nitric oxide and atrial natriuretic peptide. OT and its extended form OT-Gly-Lys-Arg have been shown to be abundant in the foetal mouse heart. OT has the capacity to generate cardiomyocytes from various types of stem cells, including the cardiac side population. Mesenchymal cells transfected with OT-Gly-Lys-Arg, or preconditioned with OT, are resistant to apoptosis and express endothelial cell markers. OT increases glucose uptake in cultured cardiomyocytes from newborn and adult rats, in normal, hypoxic and even insulin resistance conditions. In rats with experimentally-induced myocardial infarction, continuous in vivo OT delivery improves the cardiac healing process, as well as cardiac work, reduces inflammation and stimulates angiogenesis. Therefore, in pathological conditions, OT exerts anti-inflammatory and cardioprotective properties, and improves vascular and metabolic functions. Thus, OT has potential for therapeutic use., (© 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.)

Background: Four cardiac peptide hormones, namely vessel dilator, long-acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) have anticancer effects., Materials and Methods: The effects of these four cardiac hormones on human c-Jun-N-terminal kinase 2 (JNK2) were examined in human small cell lung cancer and human prostate cancer cells., Results: Vessel dilator, LANP, kaliuretic peptide and ANP maximally reduced expression of JNK2 by 89%, 56%, 45%, and 28%, respectively (each at p<0.0001) in human small cell lung cancer cells. In human prostate adenocarcinoma cells, JNK2 was maximally decreased 76%, 56%, 45%, (each at p<0.0001), and 28% (p<0.01) secondary to vessel dilator, LANP, kaliuretic peptide and ANP, respectively., Conclusion: These results indicate that four cardiac hormones are significant inhibitors (by up to 89%) of JNK2 in human small cell lung cancer cells and up to 76% in human prostate adenocarcinoma cells as part of their anticancer mechanism(s) of action.

Aims: Cardiac atrial natriuretic peptide (ANP) participates in the maintenance of arterial blood pressure and intravascular volume homeostasis. The hypovolaemic effects of ANP result from coordinated actions in the kidney and systemic microcirculation. Hence, ANP, via its guanylyl cyclase-A (GC-A) receptor and intracellular cyclic GMP as second messenger, stimulates endothelial albumin permeability. Ultimately, this leads to a shift of plasma fluid into interstitial pools. Here we studied the role of caveolae-mediated transendothelial albumin transport in the hyperpermeability effects of ANP., Methods and Results: Intravital microscopy studies of the mouse cremaster microcirculation showed that ANP stimulates the extravasation of fluorescent albumin from post-capillary venules and causes arteriolar vasodilatation. The hyperpermeability effect was prevented in mice with conditional, endothelial deletion of GC-A (EC GC-A KO) or with deleted caveolin-1 (cav-1), the caveolae scaffold protein. In contrast, the vasodilating effect was preserved. Concomitantly, the acute hypovolaemic action of ANP was abolished in EC GC-A KO and Cav-1(-/-) mice. In cultured microvascular rat fat pad and mouse lung endothelial cells, ANP stimulated uptake and transendothelial transport of fluorescent albumin without altering endothelial electrical resistance. The stimulatory effect on albumin uptake was prevented in GC-A- or cav-1-deficient pulmonary endothelia. Finally, preparation of caveolin-enriched lipid rafts from mouse lung and western blotting showed that GC-A and cGMP-dependent protein kinase I partly co-localize with Cav-1 in caveolae microdomains., Conclusion: ANP enhances transendothelial caveolae-mediated albumin transport via its GC-A receptor. This ANP-mediated cross-talk between the heart and the microcirculation is critically involved in the regulation of intravascular volume.

Purpose of Review: This review presents recent advancements in the mechanisms by which integrated signaling mechanisms elicit and regulate pancreatic endocrine and exocrine secretion., Recent Findings: Cholecystokinin (CCK) can stimulate exocrine secretion by acting directly on neurons located in the dorsal motor of the vagus or indirectly by acting on pancreatic stellate cells. The importance of small GTPases such as RhoA and Rac1 in CCK-induced pancreatic secretion is also described. Ghrelin attenuates insulin secretion through the AMP-activated protein kinase-uncoupling protein 2 pathway. An exciting new report describes that leptin can influence insulin release by osteoclastin, a hormone produced by osteoblasts. This finding adds a new layer of complexity in the regulation of insulin secretion with implications for glucose and energy homeostasis. In addition, leptin also mediates insulin secretion through the sympathetic system and via pro-opiomelanocortin neurons, which could serve as the cross-road for leptin and melanocortin signaling pathways. Recent reports on the action of numerous other regulators such as atrial natriuretic peptide, neurotensin, and orexin B are also discussed., Summary: The pancreas is an extremely complex gland. Elucidation of the secretory and regulatory pathways that control pancreatic secretion will aid in the development of treatment for diseases such as pancreatitis, diabetes, and obesity.

The discovery of the natriuretic properties of atrial muscle extracts pointed to the existence of an endocrine function of the heart that is now known to be mediated by the polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). On the basis of such a finding, approximately 27 000 publications to date have described a wide variety of biological properties of the heart hormones as well as their application as therapeutic agents and biomarkers of cardiac disease. Stimulation of secretion of ANF and BNP from the atria is mediated through mechanisms involving G proteins of the G(q) or G(o) types. We showed that the latter type underlies the transduction of muscle stretch into stimulated secretion and that it is more highly abundant in atria than in ventricles. The Gα(o)()-1 subunit appears to play a key role in the biogenesis of atrial granules and in the intracellular targeting of their contents. Protein interaction studies using a yeast two-hybrid approach showed interactions between Gα(o)()-1, proANF, and the intermediate conductance, calcium-activated K(+) channel SK4. Pharmacological inhibition of this channel decreases ANF secretion. Unpublished studies using in vitro knockdowns suggest interdependency in granule protein expression levels. These studies suggest previously unknown mechanisms of intracellular targeting and secretion control of the heart hormones that may find an application in the therapeutic manipulation of circulating ANF and BNP.

The developing heart forms during the early stages of embryogenesis, and misregulated heart development results in congenital heart defects (CHDs). To understand the molecular basis of CHDs, a deep understanding of the morphological and genetic basis of heart development is necessary. Atrial Natriuretic Factor (ANF) is an important and extremely sensitive marker for specific regions of the developing heart, as well as for disturbances in the patterning of the heart. This review summarizes the dynamic expression of ANF in the developing heart and its usefulness in understanding the early molecular defects underlying CHDs.

Atrial natriuretic peptide (ANP) has been shown to regulate lipid and carbohydrate metabolism providing a possible link between cardiovascular function and metabolism by mediating the switch from carbohydrate to lipid mobilization and oxidation. ANP exerts a potent lipolytic effect via cGMP-dependent protein kinase (cGK)-I mediated-stimulation of AMP-activated protein kinase (AMPK). Activation of the ANP/cGK signaling cascade also promotes muscle mitochondrial biogenesis and fat oxidation. Here we demonstrate that ANP regulates lipid metabolism and oxygen utilization in differentiated human adipocytes by activating the alpha2 subunit of AMPK. ANP treatment increased lipolysis by seven fold and oxygen consumption by two fold, both of which were attenuated by inhibition of AMPK activity. ANP-induced lipolysis was shown to be mediated by the alpha2 subunit of AMPK as introduction of dominant-negative alpha2 subunit of AMPK attenuated ANP effects on lipolysis. ANP-induced activation of AMPK enhanced mitochondrial oxidative capacity as evidenced by a two fold increase in oxygen consumption and induction of mitochondrial genes, including carnitine palmitoyltransferase 1A (CPT1a) by 1.4-fold, cytochrome C (CytC) by 1.3-fold, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) by 1.4-fold. Treatment of human adipocytes with fatty acids and tumor necrosis factor α (TNFα) induced insulin resistance and down-regulation of mitochondrial genes, which was restored by ANP treatment. These results show that ANP regulates lipid catabolism and enhances energy dissipation through AMPK activation in human adipocytes., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Thirty years ago, De Bold et al. (20) reported that atrial extracts contain some biologically active peptides, which promote a rapid and massive diuresis and natriuresis when injected in rats. It is now clear that the heart also exerts an endocrine function and in this way plays a key role in the regulation of cardiovascular and renal systems. The aim of this review is to discuss some recent insights and still-debated findings regarding the cardiac natriuretic hormones (CNHs) produced and secreted by cardiomyocytes (i.e., atrial natriuretic peptide and B-type natriuretic peptide). The functional status of the CNH system depends not only on the production/secretion of CNHs by cardiomyocytes but also on both the peripheral activation of circulating inactive precursor of natriuretic hormones and the transduction of the hormone signal by specific receptors. In this review, we will discuss the data supporting the hypothesis that the production and secretion of CNHs is the result of a complex integration among mechanical, chemical, hemodynamic, humoral, ischemic, and inflammatory inputs. The cross talk among endocrine function, adipose tissue, and sex steroid hormones will be discussed more in detail, considering the clinically relevant relationships linking together cardiovascular risk, sex, and body fat development and distribution. Finally, we will review the pathophysiological role and the clinical relevance of both peripheral maturation of the precursor of B-type natriuretic peptides and hormone signal transduction.

Structural remodelling occurring before, due to the underlying heart disease, and during atrial fibrillation (AF) sets the stage for permanent AF. Current therapy in AF aims to maintain sinus rhythm in symptomatic patients, but outcome is unfortunately poor. Stretch of the atria is a main contributor to atrial remodelling. In this review, we describe different aspects of structural remodelling as seen in animal models and in patients with AF, including atrial enlargement, cellular hypertrophy, dedifferentiation, fibrosis, apoptosis, and loss of contractile elements. In the second part, we describe downstream signals of mechanical stretch and their contribution to AF and structural remodelling. Ultimately, knowledge of mechanisms underlying structural remodelling may help to identify new pharmacological targets for AF prevention.

The acute acclimatization to high altitude is underpinned by a diuresis (and to a lesser extent a natriuresis) that facilitates a reduction in plasma volume. This allows a haemoconcentration to occur that increases the oxygen carrying capacity of a given volume of blood, a vital effect in the presence of a reduced partial pressure of oxygen. This critical acclimatization process is orchestrated by the endocrine system. This review will present the key evidence regarding the changes in several important hormones that affect this process.

Atrial natriuretic peptide (ANP) plays an important role in the pathophysiology of the vascular complications in diabetes. The working hypothesis was that diabetes might modify the vascular actions of ANP in isolated rabbit carotid arteries and the mechanisms involved in these actions. ANP (10(-12)-10(-7)M) induced a relaxation of precontracted carotid arteries, which was lower in diabetic than in control rabbits. In arteries from both groups of animals, endothelium removal increased the ANP-induced relaxation. Isatin inhibited the relaxation to ANP both in arteries with and without endothelium. Carotid arteries from diabetic rabbits showed a decreased natriuretic peptide receptor (NPR)-A expression and an enhanced NPR-C expression. Inhibition of NO-synthesis did not modify ANP-induced relaxation in control rabbits but inhibited it in diabetic rabbits. In arteries with endothelium indomethacin enhanced the relaxation to ANP in control rabbits but did not modify it in diabetic rabbits. In endothelium-denuded arteries indomethacin inhibited the relaxation to ANP in both groups of animals. In KCl-depolarised arteries, relaxation to ANP was almost abolished both in control and diabetic rabbits. Tetraethylammonium inhibited the relaxation to ANP, and this inhibition was higher in diabetic than in control rabbits. These results suggest that diabetes produces hyporeactivity of the rabbit carotid artery to ANP by a mechanism that at least includes a reduced expression of NPR-A, an enhanced expression of NPR-C and a reduced participation of K(+)-channels. Furthermore, diabetes enhances endothelial NO release and diminishes the ratio thromboxane A(2)/prostacyclin. This increase of vasodilators could result from compensatory mechanisms counteracting the arterial hyporeactivity to ANP., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: Increased levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have been shown to reduce the hormones in the HPA axis. In this study we addressed the question whether patients with unmedicated major depressive disorder (MDD) might have altered baseline levels of these natriuretic peptides and an altered response to acute exercise., Methods: An incremental exercise test was performed in 18 patients with MDD and in 18 healthy controls. Plasma concentrations of ANP and BNP were determined at rest, during the exercise test and 30 min post exercise using immunoradiometric assays., Results: During the exercise test the concentrations of ANP and BNP increased significantly in both groups. The MDD group showed significantly lower levels of ANP than the controls at rest, at maximal work rate and post exercise and of BNP at rest and at maximal work rate. The dynamic changes of both ANP and BNP, respectively, from baseline to maximal work rate were significantly lower in the MDD group. A slightly lower (non-significant) maximal work rate was observed in the MDD group compared with the controls., Limitations: Group sizes are relatively limited., Conclusion: Lower concentrations of ANP and BNP during rest and exercise were observed in the MDD patients together with a decreased dynamic response to maximal exercise. Hypothetically, the reduced ANP and BNP concentration contributes to the high hormone levels in the HPA system seen in depressive disorders. Of interest for future research is whether physical training might increase the levels of ANP and BNP and thereby diminish depressive symptoms., (Copyright © 2010 Elsevier B.V. All rights reserved.)

During heart development chamber specification is controlled and directed by a number of genes and a fetal heart gene expression pattern is revisited during heart failure. In the setting of chronic pulmonary hypertension the right ventricle undergoes hypertrophy, which is likely initially adaptive, but often followed by decompensation, dilatation and failure. Here we discuss differences between the right ventricle and the left ventricle of the heart and begin to describe the cellular and molecular changes which characterize right heart failure. A prevention and treatment of right ventricle failure becomes a treatment goal for patients with severe pulmonary hypertension it follows that we need to understand the pathobiology of right heart hypertrophy and the transition to right heart failure., (© 2011 American Physiological Society.)

The renin-angiotensin system (RAS) is critically involved in the regulation of the salt and volume status of the body and blood pressure. The activity of the RAS is controlled by the protease renin, which is released from the renal juxtaglomerular epithelioid cells into the circulation. Renin release is regulated in negative feedback-loops by blood pressure, salt intake, and angiotensin II. Moreover, sympathetic nerves and renal autacoids such as prostaglandins and nitric oxide stimulate renin secretion. Despite numerous studies there remained substantial gaps in the understanding of the control of renin release at the organ or cellular level. Some of these gaps have been closed in the last years by means of gene-targeted mice and advanced imaging and electrophysiological methods. In our review, we discuss these recent advances together with the relevant previous literature on the regulation of renin release.