C-type natriuretic peptide in vascular physiology and disease

Natriuretic peptides play a critical role in coordination of fluid/electrolyte balance and vascular tone. The renal effects of circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are distinct from the paracrine effects of vascular C-type natriuretic peptide (CNP). CNP is widely expressed throughout the vasculature and is found in particularly high concentrations in the endothelium. Recent studies demonstrate that CNP is a novel endothelium-derived hyperpolarising factor (EDHF) that complements the actions of other endothelial vasorelaxant mediators such as nitric oxide (NO) and prostacyclin. Since several cardiovascular disorders are associated with dysfunction of natriuretic peptide activity, selective modulation of the natriuretic peptide pathways represents an important therapeutic target; whilst this has been exploited to some degree in terms of ANP/BNP, the therapeutic potential of CNP has yet to be tapped. This review focuses on recent findings on the actions and mechanism of locally produced endothelial-derived CNP in the cardiovascular system and highlights many potential avenues for therapeutic intervention, via modulation of CNP-signalling, in cardiovascular disease.     

Structure and function of ventricular natriuretic peptide (VNP)]

Ventricular natriuretic peptide (VNP) appears to be a new member of the ANP family, as judged by its uniquely long C-terminal 'tail' sequence and by its cDNA sequence. The eel VNP causes the entire spectra of actions known to be characteristic of the ANP family, and its vascular and renal effects are more potent than other eel natriuretic peptides in both eels and rats. Since VNP is a hormone originating from ventricles, it is possible that VNP is secreted more quickly and profoundly than atrium-originated ANP, in response to an increase in afterload or stenosis of the coronary artery, resulting in recovery of ventricular function. Therefore, identification of VNP in mammals is awaited for the development of a new drug which counteracts against heart failure.     

Atrial natriuretic peptide and related peptides.

In recent years, biomarkers have been recognized as important tools for diagnosis, risk stratification, and therapeutic decision-making in cardiovascular diseases. Currently, the clinical potential of several natriuretic peptides is under scientific investigation. The well-known counter-regulatory hormones are atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP) and urodilatin, which play an important role in the homeostasis of body fluid volume. ANP and BNP have already been demonstrated to have diagnostic usefulness in a great number of studies, which have progressed from bench to bedside. This article summarizes existing data on ANP and related peptides in cardiovascular and other disorders, and outlines the potential clinical usefulness of these markers.     

Autocrine and paracrine actions of natriuretic peptides in the heart

The natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), are a family of polypeptide mediators exerting numerous actions in cardiovascular homeostasis. ANP and BNP are cardiac derived, being secreted and up-regulated in myocardium in response to many pathophysiological stimuli. CNP is an endothelium-derived mediator. The classical endocrine effects of ANP and BNP on fluid homeostasis and blood pressure, especially in conditions characterised by left ventricular dysfunction, are well recognised and extensively researched. However, there is accumulating evidence that, in addition to endocrine actions, ANP and BNP exhibit important autocrine and paracrine functions within the heart and coronary circulation. These include regulation of myocyte growth, inhibition of fibroblast proliferation and extracellular matrix deposition, a cytoprotective anti-ischaemic (preconditioning-like) function, and influences on coronary endothelium and vascular smooth muscle proliferation and contractility. Most if not all of these actions can be ascribed to particulate guanylyl cyclase activation because the ANP/BNP receptor, natriuretic peptide receptor (NPR)-A, has an intracellular guanylyl cyclase domain. Subsequent elevation of the intracellular second messenger cGMP may exert diverse physiological effects through activation of cGMP-dependent protein kinases (cGK), predominantly cGK-I. However, there appear to be other contributory mechanisms in several of these actions, including the augmentation of nitric oxide synthesis. These diverse actions may represent counterregulatory mechanisms in the pathophysiology of many cardiovascular diseases, not just those typified by left ventricular dysfunction. Ultimately, insights from the autocrine/paracrine actions of natriuretic peptides may provide routes to therapeutic application in cardiac diseases of natriuretic peptides and drugs that modify their availability.     

Atrial and brain natriuretic peptides stimulate the production and secretion of C-type natriuretic peptide from bovine aortic endothelial cells.

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family which is produced in vascular endothelial cells and may play an important paracrine role in the vasaculature. We sought to determine the regulation of CNP production by other vasoactive peptides from cultured aortic endothelial cells. The vasoconstrictors endothelin-1 and angiotensin II had little effect on the basal secretion of CNP. In contrast, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) strongly stimulated the secretion of CNP. BNP caused as much as a 400-fold enhancement above the basal accumulated secretion of CNP over 24 h at a concentration of 1 microM; this was 20 times greater than the stimulatory effect of ANP, BNP and ANP also significantly enhanced the production of new CNP protein (translation) and mRNA expressed in the BAEC. In contrast, C-ANP-4-23, a truncated form of ANP which selectively binds to the natriuretic peptide clearance receptor, did not stimulate CNP secretion. The enhanced production and secretion of CNP, caused by either ANP or BNP, was significantly prevented by LY 83583, an inhibitor of cGMP generation, and was also attenuated by KT 5823, an inhibitor of cGMP-dependent protein kinase. Our results indicate that ANP and BNP can stimulate CNP production through a guanylate cyclase receptor on endothelial cells. BNP is a much more potent stimulator of CNP secretion, compared to ANP. Our findings suggest that the vasodilatory, and anti-mitogenic effects of ANP and BNP in the vasculature could occur in part through CNP production and subsequent action if these interactions occur in vivo.     

Implications of the natriuretic peptide system in the pathogenesis of heart failure: diagnostic and therapeutic importance

The natriuretic peptide family consists of at least 3 structurally similar peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Under normal conditions, ANP is synthesized by the atrium and released in response to atrial stretch. This peptide plays an important role in sodium and water homeostasis and is involved in cardiovascular function. In contrast, BNP is synthesized primarily by the ventricles, and its circulatory concentrations are significantly elevated in profound congestive heart failure (CHF). While both plasma levels of ANP and BNP have been found to be increased in patients with various heart diseases, the elevation in circulatory BNP correlates better than ANP with the severity of CHF. Therefore, plasma BNP has been suggested (and lately used) to aid in the accurate diagnosis of heart failure in patients admitted to the emergency room with symptoms of decompensated heart failure. Furthermore, circulatory BNP has been utilized as a prognostic marker in CHF as well as a hormone guide in the evaluation of the efficacy of the conventional treatment of this disease state. In light of the cardiovascular and renal effects of BNP, which most likely exceed those of ANP, the former has been used as a therapeutic agent for the treatment of patients with acute severe CHF. Intravenous infusion of BNP into patients with sustained ventricular dysfunction causes a balanced arterial and venous vasodilatation that has been shown to result in rapid reduction in ventricular filling pressure and reversal of heart failure symptoms, such as dyspnea and acute hemodynamic abnormalities. Thus, the goal of this article is to review the physiology and pathophysiology of natriuretic peptides and the potential use of their circulating levels for diagnosis and treatment of heart failure.     

Cross-talk between the natriuretic peptide system and the angiotensin system

The natriuretic peptide comprises at least three ligands(ANP, BNP, and CNP) and three receptors(GC-A, GC-B, and Clearance receptor). ANP and BNP are cardiac hormones, which regulate blood pressure and body fluid volume. Angiotensin II, the effector peptide of the renin-angiotensin system, regulates cellular growth in response to developmental, physiological and pathological processes. Recently, evidences suggest that cardiovascular homeostasis is determined by the balance between these two important counter-regulatory pathways. In this paper, we will discuss the molecular mechanism of the cross-talk between the two systems, including our recent findings using the mice deficient for GC-A and angiotensin II receptors. The results suggest that the endogenous natriuretic peptide system inhibits the cardiac angiotensin system and protects the heart from excessive pathological remodelings.     

Molecular biology of the natriuretic peptide system]

The natriuretic peptide system is composed of at least three distinct endogenous peptides: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and three receptors: ANP-A receptor/GC-A, ANP-B receptor/GC-B and the clearance receptor. This system influences the control of body fluid and blood pressure as cardiac hormones and local regulators. Recent advances in molecular biology have unravel the molecular mechanism of the natriuretic peptide system and have facilitated our understanding of it. The present review gives the current knowledge of the molecular biology of the natriuretic peptide system.     

Bremazocine increases C-type natriuretic peptide levels in aqueous humor and enhances outflow facility

A relatively selective agonist of kappa opioid receptors (KOR), bremazocine (BRE), lowers intraocular pressure in rabbits, in part, by increasing natriuretic peptide levels in aqueous humor and by enhancing total outflow facility (TOF). Natriuretic peptide (NP) levels [atrial NP (ANP), brain NP (BNP), and C-type NP (CNP)] were measured in aqueous humor of rabbits either by radioimmunoassay or enzyme immunoassay. TOF was determined in rabbits by two-level constant pressure perfusion of the anterior chamber. Experimental regimens included topical treatment with BRE in the presence or absence of KOR antagonist (norbinaltorphimine), protein kinase C inhibitor (chelerythrine), and natriuretic peptide receptor antagonist (isatin). The rank order of basal NP levels in aqueous humor of rabbits was BNP CNP > ANP. Topical administration of BRE (1-100 microg) caused dose-related elevations of CNP levels in aqueous humor that were inhibited by topical pretreatment with either norbinaltorphimine (100 microg, bilaterally) or chelerythrine (10 microg, bilaterally). Topically administered BRE (100 microg) also elevated levels of ANP and BNP in aqueous humor and evoked an 80% increase in TOF. The increase in TOF was antagonized by topical pretreatment with either norbinaltorphimine (100 microg, bilaterally) or isatin (100 microg, bilaterally). Bremazocine induced an increase in NP (ANP, BNP, and CNP) levels and TOF in rabbits by activating KOR. The increase in CNP levels elicited by BRE was inhibited by norbinaltorphimine and chelerythrine; therefore, this event is most likely mediated by a KOR-linked activation of protein kinase C. These data provide evidence that the increase in TOF elicited by BRE was mediated by a KOR-activated paracrine effect of NPs on tissues within ocular outflow tract(s).     

等张运动和抗阻运动对血浆利钠肽激素的影响

目的 :比较等张运动和抗阻运动对血浆利钠肽激素的影响。方法 :8例健康男性采用相同靶心率和相同运动时间 ,分别进行等张运动和交替抗阻运行 ,观察运动前后血浆利钠肽的应激变化。结果 :血浆心房利钠肽和脑利钠肽在等张运动后并行性显著增高 ,抗阻运动后增高不明显 ,但其分泌程度与两项乘积呈正相关。结论 :运动可以导致血浆利钠肽激素的增高 ,体内各激素水平之间存在着交互抑制的现象 ,两种运动形式均有利于提高冠状血管的贮备功能     

Natriuretic peptide system: physiology and clinical utility

PURPOSE OF REVIEW: This review discusses the physiology of natriuretic peptides as a group and brain natriuretic peptide (BNP) in more detail. It will also highlight implications for the use of the natriuretic peptides in the diagnosis and treatment of patients with cardiovascular disease. RECENT FINDINGS: The heart secretes two major natriuretic peptides: atrial natriuretic peptide (ANP), which is synthesized in the atrial myocardium, and BNP, which is synthesized in the ventricular myocardium. Both ANP and BNP are released in response to atrial and ventricular stretch, respectively, and will cause balanced vasodilation, natriuresis, and inhibition of the sympathetic nervous system and the renin-angiotensin-aldosterone axis. BNP is reported to be the biochemical marker of choice for evaluating the acute risk of patients with cardiovascular disease states ranging from heart failure to myocardial ischemia. Increased blood BNP concentrations are highly predictive of the short- and long-term risk of cardiac death across the entire spectrum of acute coronary syndromes and in patients with decompensated congestive heart failure. Synthetic recombinant human BNP, which mimics the actions of endogenous BNP, has emerged as an important new therapeutic agent in patients with acute heart failure. SUMMARY: Current data suggest that single and serial plasma measurement of BNP concentrations is a useful tool in the diagnosis and risk stratification of patients with heart disease. Nesiritide, the human recombinant form of BNP, is a new promising parenteral treatment in decompensated heart failure.     

Expression and differential regulation of natriuretic peptides in mouse macrophages.

The coexpression of the natriuretic peptides ANP, BNP and CNP as well as their differential regulation in mouse macrophages was demonstrated by quantitative PCR, HPLC analysis, and specific radioimmunoassays. Exposure of peritoneal- and bone marrow-derived macrophages to various immunomodulators revealed that bacterial LPS strikingly increases (up to 300-fold) the mRNA coding for CNP as does zymosan (up to 15-fold). In this respect, neither the phorbol ester PMA nor the glucocorticoid dexamethasone had any effect. Examination of macrophages for ANP mRNA showed a similar response to LPS and zymosan, though only a three- to sixfold increase, confirming previous data. In contrast, the concentration of mRNA coding for brain natriuretic peptide in these cells was reduced by dexamethasone (up to twofold) as well as LPS (two- to fivefold). No change was observed upon challenge with zymosan or PMA. The findings at the mRNA level are complemented by their corresponding peptide products. Incubation of macrophages with LPS resulted in a two- and fivefold elevation of intracellular ANP and CNP immunoreactivity, respectively. The amount of peptides released from cells under these conditions was found increased for ANP (threefold) and CNP (10-fold). No changes were observed for both intra- and extracellular brain natriuretic peptide. The coexpression of natriuretic peptides in macrophages as well as their different regulations by immunomodulators suggest discrete functions of these peptides within the immune system.     

C-type natriuretic peptide does not affect plasma and urinary adrenomedullin in man

To investigate whether C-type natriuretic peptide (CNP) at pathophysiological plasma levels stimulates the release of adrenomedullin (ADM) in man, six healthy subjects (three men and three women, mean age 35 ± 3 years, range 33–40 years) received an intravenous infusion of synthetic human CNP-22 (2 pmol kg^?1 min for 2 h), in a single-blind, placebo-controlled, random order, cross-over study, with measurements of the plasma levels of cyclic guanosine monophosphate (cGMP), ADM, renin and atrial natriuretic peptide (ANP), arterial pressure, heart rate, renal blood flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and the urinary excretion rates of cGMP, ADM and sodium. Infusion of CNP induced increases in its own levels (from 1·17 ± 0·11 up to 21·13 ± 1·41 pmol l^?1) without modifying the plasma levels of cGMP, ADM, renin and ANP, the urinary excretion rate of ADM and cGMP, renal haemodynamics and sodium excretion. These data indicate that circulating CNP is not involved in the regulation of ADM release, renal haemodynamics and sodium excretion in man.     

Endothelial C-type natriuretic peptide maintains vascular homeostasis

The endothelium plays a fundamental role in maintaining vascular homeostasis by releasing factors that regulate local blood flow, systemic blood pressure, and the reactivity of leukocytes and platelets. Accordingly, endothelial dysfunction underpins many cardiovascular diseases, including hypertension, myocardial infarction, and stroke. Herein, we evaluated mice with endothelial-specific deletion of Nppc, which encodes C-type natriuretic peptide (CNP), and determined that this mediator is essential for multiple aspects of vascular regulation. Specifically, disruption of CNP leads to endothelial dysfunction, hypertension, atherogenesis, and aneurysm. Moreover, we identified natriuretic peptide receptor–C (NPR-C) as the cognate receptor that primarily underlies CNP-dependent vasoprotective functions and developed small-molecule NPR-C agonists to target this pathway. Administration of NPR-C agonists promotes a vasorelaxation of isolated resistance arteries and a reduction in blood pressure in wild-type animals that is diminished in mice lacking NPR-C. This work provides a mechanistic explanation for genome-wide association studies that have linked the NPR-C (Npr3) locus with hypertension by demonstrating the importance of CNP/NPR-C signaling in preserving vascular homoeostasis. Furthermore, these results suggest that the CNP/NPR-C pathway has potential as a disease-modifying therapeutic target for cardiovascular disorders.     

Angiotensin II and atrial natriuretic peptide in the brain: effects on volume and Na+ balance

Atrial natriuretic peptide (ANP) and angiotensin II (ANG II), although originally isolated from peripheral sources, are now known to be present in the central nervous system. The distribution of the peptides and their binding sites are found in areas involved in cardiovascular and volume/electrolyte regulation. Since ANP administered centrally can antagonize the actions of ANG II, the two peptides may function as opposing mechanisms involved in maintaining fluid and electrolyte homeostasis.     

Natriuretic peptide-induced relaxation of myometrium from the pregnant guinea pig is not mediated by guanylate cyclase activation

We tested both relaxation and cGMP generation by atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) in oxytocin-stimulated myometrium from near-term pregnant guinea pigs to investigate the ability and mechanism of natriuretic peptides to inhibit myometrial contractility. Myometrial strips were contracted by 10(-8) M oxytocin, and relaxation to the cumulative addition (10(-9)-10(-6) M) of the natriuretic peptides measured. Maximal relaxation to BNP was significantly greater than to ANP (52 versus 32% respectively; p < 0.05), whereas CNP failed to produce relaxation. However, the increase in cGMP produced by BNP (10(-7) M) was significantly less than that produced by ANP (10(-7) M) (4.5 versus 7.0 times basal; p < 0.05); CNP did not increase myometrial cGMP. Anantin, a competitive blocker of the guanylate cyclase A receptor, significantly reduced the increase in cGMP produced by ANP and BNP, but had no effect on relaxation induced by either peptide. Rp-8-Br-cGMP, an inhibitor of the cGMP-dependent protein kinase, did not alter BNP-induced relaxation. The atrial natriuretic peptide-fragment 4-23 amide, a natriuretic peptide clearance receptor agonist, failed to inhibit oxytocin-stimulated myometrial contraction. We conclude that natriuretic peptide induced relaxation of oxytocin-stimulated myometrium from the pregnant guinea pig is not mediated by either guanylate cyclase A or B activation, is independent of the cGMP pathway, and does not involve clearance receptor activation. Our results suggest that natriuretic peptide-induced relaxation of pregnant myometrium is mediated via a novel mechanism.     

Heart specific up-regulation of genes for B-type and C-type natriuretic peptide receptors in diabetic mice

BACKGROUND: Diabetes may cause cardiomyopathy characterized by cardiac fibrosis. Recent studies of genetically modified mice have elucidated a role of the natriuretic peptides (NP), type-A and type-B (ANP and BNP), and their common receptor [natriuretic peptide receptor (NPR), type-A] in development of cardiac fibrosis. The role of NP type-C (CNP) and NPR type-B (NPR-B) in the heart is less well established. In this study we examined if diabetes alters heart expression of the genes encoding the NP and its receptors. MATERIALS AND METHODS: Cardiac mRNA was quantified by real-time PCR in diabetic streptozotocin (STZ)-treated and ob/ob-mice and nondiabetic control mice. RESULTS: The ob/ob-mice with type-II diabetes displayed highly significant increases of the cardiac mRNA expression of NPR-B and NPR-C while the expression levels of NPR-A, ANP, BNP, and CNP mRNA were similar in ob/ob-mice and controls. Mice with STZ-induced type-I diabetes also showed an increase of heart NPR-B mRNA expression at 12 weeks, but not at 3, 6 or 9 weeks after STZ-treatment. The ANP and NPR-C mRNA expressions were only altered after 3 weeks, whereas BNP, CNP and NPR-A mRNA expressions were not altered in STZ-treated-mouse hearts at any of the time points. CONCLUSIONS: The results show that diabetes in mice confers increased NPR-B gene expression in the heart, suggesting that increased NPR-B signalling may affect development of diabetic cardiomyopathy.     

Increased plasma levels of NT-proANP and NT-proBNP as markers of cardiac dysfunction in septic patients

The family of natriuretic peptides comprises several structurally related 22-53-amino acid peptides, such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are vasoactive peptides with vasodilator and diuretic properties and play an important role in cardiovascular homeostasis. The salutary cardiovascular effects of natriuretic peptides suggest that ANP and BNP may have a pathophysiological significance in the cardiac dysfunction of septic patients. We determined plasma levels of the stable N-terminal prohormone forms of ANP (NT-proANP) and BNP (NT-proBNP) as well as troponin I (TNI) as a marker of myocardial cell injury by ELISA methods in 19 septic patients and 19 healthy controls at day one of severe sepsis. Left ventricular ejection fraction (LVEF) was determined on day 1 of severe sepsis by echocardiography. Significantly higher concentrations of NT-proANP were measured in non-survivors (mean = 13415 pmol/l +/- SEM = 4295) and survivors (mean = 7386 pmol/l +/- SEM = 1807) as compared to controls (mean = 1404 pmol/l +/- SEM = 181; p<0.001). Levels of NT-proBNP were also significantly higher in non-survivors (mean = 3439 pmol/l +/- SEM = 1246; p<0.05) and survivors (mean = 1009 pmol/l +/- SEM = 263; p<0.001) as compared to controls (mean = 200 pmol/l +/- SEM = 24) and correlated well with an increase in TNI-levels (r = 0.71; p<0.001). NT-proANP and NT-proBNP may serve as useful laboratory markers to indicate myocardial dysfunction and may help to differentiate between survivors and non-survivors of severe sepsis.