De Bold Research Articles

Atrial Natriuretic Peptide, Heart Failure and the Heart as an Endocrine Organ.

Featured Article: Burnett JC Jr, Kao PC, Hu DC, Heser DW, Heublein D, Granger JP, et al. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science 1986;231:1145–7.3 Thirty-three years ago, we reported the increase of circulating atrial natriuretic peptide (ANP)4 in human heart failure (HF). This report, which is featured here, was published 5 years after the landmark work of de Bold that established the heart as an endocrine organ with the discovery of ANP, which he originally named atrial natriuretic factor (1). Indeed, what followed has been a transformational journey that has changed our thinking of the heart as more than a pump and has contributed to the clinical development of a second cardiac natriuretic peptide, b-type natriuretic peptide (BNP), as the gold standard in HF diagnosis. The work of Waldman and Murad importantly established that ANP activated the particulate guanylyl cyclase A receptor resulting in the production of the second messenger, 3′,5′ cyclic guanosine …

The renal and cardiovascular effects of natriuretic peptides.

The landmark report by de Bold et al. in 1981 signified the heart as one of the endocrine organs involved in fluid and salt balance (de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. Life Sci 28: 89-94, 1981). Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are secreted from cardiomyocytes in response to cardiac stretch as in the case of heart failure, whereas C-type natriuretic peptide (CNP) is secreted from endothelial and renal cells in response to cytokines and endothelium-dependent agonists, such as acetylcholine. Binding ANP or BNP to natriuretic peptide receptor A induces cyclic guanylyl monophosphate as second messenger in the target cells to mediate the following: natriuresis; water diuresis; increasing glomerular filtration rate; decreasing systemic sympathetic activities; plasma volume; cardiac output and blood pressure; and curbing mitoses of heart fibroblasts and hypertrophy of cardiovascular muscle cells. ANP, BNP, and CNP are cleared from the bloodstream by natriuretic peptide receptor C and degraded by an ectoenzyme called neprilysin (NEP). The plasma levels of BNP are typically >100 pg/ml in patients with congestive heart failure. Sacubitril/valsartan is an angiotensin receptor NEP inhibitor that prevents the clinical progression of surviving patients with heart failure more effectively than enalapril, an angiotensin-converting enzyme inhibitor. A thorough understanding of the renal and cardiovascular effects of natriuretic peptides is of major importance for first-year medical students to gain insight into the significance of plasma levels of BNP in patients with heart failure.

2015 European Society of Cardiology Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death summarized by co-chairs.

The present European Society of Cardiology (ESC) Guidelines is a European update to the 2006 European/American guidelines for the management of patients with ventricular arrhythmias (VA) and the prevention of sudden cardiac death (SCD). The update is timely considering new insights into the natural history of diseases predisposing to SCD especially for younger individuals and also with the completion of major trials that have impacted management strategies for heart failure (HF).

Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events.

Atrial natriuretic peptide (ANP), B‐type natriuretic peptide (BNP), and C‐type natriuretic peptide (CNP) are the known members of the mammalian natriuretic peptide system. The discovery of natriuretic peptides (NPs) dates back to 1981, when de Bold et al. found that administration of atrial

Lessons from health research luminaries.

What do leading health researchers know that others don’t? The legacies of three of Canada’s most celebrated scientists provide a few clues. Canadian Medical Hall of Fame 2014 laureates Adolfo de Bold, Ronald Worton and Max Cynader cite perseverance, collaboration and an entrepreneurial spirit

The heart‐liver metabolic axis: defective communication exacerbates disease

The heart has been recognized as an endocrine organ for over 30 years (de Bold, 2011); however, little is known about how the heart communicates with other organs in the body, and even less is known about this process in the diseased heart. In this issue of EMBO Molecular Medicine, Magida and Leinwand (2014) introduce the concept that a primary genetic defect in the heart results in aberrant hepatic lipid metabolism, which consequently exacerbates hypertrophic cardiomyopathy (HCM). This study provides evidence in support of the hypothesis that crosstalk occurs between the heart and liver, and that this becomes disrupted in the diseased state.

Natriuretic peptide receptors and heart failure: to B or not to B blocked?

The role of natriuretic peptides in the dynamic regulation ofblood volume and pressure is now well established and com-prises the complementary endocrine actions of atrial (ANP)and brain (BNP) natriuretic peptides, with the more local,paracrine bioactivity of C-type natriuretic peptide (CNP).This family of mediators also coordinates to maintain cardiacfunction and integrity (Potter et al. 2009). However, muchof the information pertaining to the physiological functionsof these peptides has not been garnered via the use ofselective pharmacological tools. Indeed, there are a paucityof such reagents and this has been the bane of researchersin the field for their inception with the identification ofANP in 1981(de Bold et al. 1981). Several selective agonistsand antagonists at natriuretic peptide receptors (NPRs), themembrane spanning proteins that transduce signals conveyedby natriuretic peptides, have been described, but the vastmajority are high molecular weight, often peptide-based,molecules with suboptimal pharmacodynamic and pharma-cokinetic properties.Perhaps the most useful tool to date has been HS-142-1, apolysaccharide extracted from Aureobasidium sp. (Morishitaet al. 1991).This reagent inhibitsactivationof bothguanylatecyclase-coupled NPRs (i.e. NPR-A and NPR-B) through anallosteric interaction, but does not bind NPR-C (Poirier et al.2002). It has therefore been an ideal intervention to definemechanisms reliant on the activation of particulate guanylatecyclases(andtodifferentiate between these membrane-boundisoforms and the NO-sensitive soluble guanylate cyclase).Regrettably, the production of HS-142-1 has now beenhalted and is no longer available. Several additional moleculeshave been reported to selectively inhibit NPR-A (the cognatereceptorforANPandBNP,e.g.A71915(Delporteetal. 1992),S-28-Y (Minamitake et al. 1990), anantin (Weber et al. 1991;Wyssetal. 1991)andPL-3994(Edelsonetal. 2013))orNPR-B(the cognate receptor for CNP, e.g. a monoclonal antibody3G12 (Drewett et al. 1995) and P19 (Deschenes et al. 2005)).A truncated, modified natriuretic peptide, cANF

AB0892 NT-PROBNP in ankylosing spondylitis patients undergoing TNF blockage therapy: Correlation with inflammatory status independent of cardiovascular disease

BackgroundInflammation may influence levels of N-terminal pro-brain natriuretic peptide (NT-proBNP)1-3 discrimination of this confounding variable is of particular interest in rheumatic diseases.4ObjectivesWe evaluated NT-proBNP levels in ankylosing spondylitis (AS) patients...

Phosphodiesterase 4 inhibition attenuates plasma volume loss and transvascular exchange in volume expanded mice

Phosphodiesterase 4 inhibition attenuates plasma volume loss and transvascular exchange in volume expanded mice

Thirty years of the heart as an endocrine organ: physiological role and clinical utility of cardiac natriuretic hormones

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.

Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides

The mammalian natriuretic peptide family consists of atrial (ANP), brain [B-type; BNP] and C-type natriuretic peptide (CNP) and three receptors, natriuretic receptors-A (NPR-A), -B (NPR-B) and -C (NPR-C). Both ANP and BNP are abundantly expressed in the heart and are secreted mainly from the atria and ventricles, respectively. By contrast, CNP is mainly expressed in the central nervous system, bone and vasculature. Plasma concentrations of both ANP and BNP are elevated in patients with cardiovascular disease, though the magnitude of the increase in BNP is usually greater than the increase in ANP. This makes BNP is a clinically useful diagnostic marker for several pathophysiological conditions, including heart failure, ventricular remodeling and pulmonary hypertension, among others. Recent studies have shown that in addition to BNP-32, proBNP-108 also circulates in human plasma and that levels of both forms are increased in heart failure. Furthermore, proBNP-108 is O-glycosylated and circulates at higher levels in patients with severe heart failure. In this review we discuss recent progress in our understanding of the biochemistry, molecular biology and clinical relevance of the natriuretic peptide system.

From humans to giraffes: The evolution of hypertension and hormones

From humans to giraffes: The evolution of hypertension and hormones

Natriuretic Peptide Testing in Clinical Medicine

Since the discovery of atrial natriuretic factor in 1981 by de Bold et al, there has been tremendous progress in our understanding of natriuretic peptides (NPs). Recently, testing for brain-type NP (BNP) and its amino terminal cleavage equivalent (NT-proBNP) has been rapidly adopted in clinical medicine for numerous indications, including the diagnosis and exclusion of heart failure (HF). In this regard, logical application of BNP or NT-proBNP testing may not only reduce healthcare costs but also potentially reduce adverse clinical outcomes. With respect to this fact, the potential importance of the concentration of the NPs for prognosis and the response of BNP or NT-proBNP to therapeutic intervention in terms of clinical events has been demonstrated. On the basis of these observations it is reasonable to expect that concentrations of these peptides might be useful for the management of patients with HF, acting as a gauge of therapeutic accuracy and/or stability of disease. Besides HF, the prognostic utility of NPs has been explored in other settings, particularly in ischemic heart disease and those conditions that lead to right ventricular dysfunction.

Natriuretic Peptides

In the 25 years since de Bold et al demonstrated the existence of an atrial natriuretic factor, investigation of the cardiac natriuretic peptides has produced a maturing knowledge base1,2 identifying the cardiac peptides and addressing stimuli for secretion of atrial (ANP) and B-type (BNP) natriuretic peptides, the processing and release of the mature bioactive carboxy terminal peptides, together with their propeptides and amino terminal fragments, the nature of natriuretic peptide receptors, and the bioactivities of natriuretic peptides (including natriuresis, vasodilatation, suppression of renin–angiotensin–aldosterone and sympathetic nervous activity, and trophic effects inhibiting vascular and cardiac hypertrophy and fibrosis). Less is known of the more recently discovered C-type natriuretic peptide (CNP and its cosecreted amino-terminal peptide, NTproCNP).3,4 Increasingly, measurements of the B-type peptides have found diagnostic and prognostic application in cardiovascular disease.5–7 The genes for ANP and BNP are in tandem on human chromosome 1.8 Upstream regulatory regions identified for the BNP gene include an AP1 binding site, serum response elements, M-CAT and GATA sites.9,10 Translation results in pre-pro BNP from which a 26 amino acid signal peptide is cleaved to produce the 108 amino acid precursor proBNP. This in turn is processed between amino acid residues 76 and 77 resulting in a 32 amino acid biologically active peptide (BNP) from its carboxy terminal plus the remaining amino terminal peptide sequence (NTproBNP 1 to 76). ANP is synthesized as a 126 amino acid precursor and is stored in granules within atrial tissue.11 During or shortly after secretion, the precursor is processed to an active 28 amino acid carboxy terminal peptide (ANP) and amino terminal ANP (proANP 1 to 98). The amino terminal propeptides NTproANP, NTproBNP, and NTproCNP have no known biological actions. The mature bioactive human forms of ANP, BNP, and CNP all contain a 17 …

Natriuretic peptides and therapeutic applications

Since the discovery of atrial natriuretic factor by de Bold et al., there has been tremendous progress in our understanding of the physiologic, diagnostic and therapeutic roles of the natriuretic peptides (NPs) in health and disease. Natriuretic peptides are endogenous hormones that are released by the heart in response to myocardial stretch and overload. Three mammalian NPs have been identified and characterized, including atrial natriuretic peptide (ANP or atrial natriuretic factor), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In addition, Dendroaspis natriuretic peptide (DNP) has been isolated from the venom of Dendroaspis angusticeps (the green mamba snake), and urodilatin from human urine. These peptides are structurally similar and they consist of a 17-amino-acid core ring and a cysteine bridge. Both ANP and BNP bind to natriuretic peptide receptor A (NPR-A) that are expressed in the heart and other organs. Activation of NPR-A generates an increase in cyclic guanosine monophosphate, which mediates natriuresis, inhibition of renin and aldosterone, as well as vasorelaxant, anti-fibrotic, anti-hypertrophic, and lusitropic effects. The NP system thus serves as an important compensatory mechanism against neurohumoral activation in heart failure. This provides a strong rationale for the use of exogenous NPs in the management of acutely decompensated heart failure. In this article, the therapeutic applications of NPs in the acute heart failure syndromes are reviewed. Emerging therapeutic agents and areas for future research are discussed.

Natriuretic peptide measurements as part of the diagnostic work-up in pleural effusions: an emerging concept?

In the 1950s and 60s, the possible role of the heart in the control of renal excretion of salt and water, and thereby of the extra cellular fluid volume, as well as the presence of specific granules within atrial muscle cells was recognised 1,2. Nevertheless, little attention was paid to the possibility of the existence of an endocrine cardiac natriuretic hormone system until the landmark experiments in the late 1970s by de Bold et al. 3, which led to the discovery of atrial natriuretic peptide (A-type natriuretic peptide; ANP) having potent natriuretic, diuretic and vasodilatator actions. This initiated intense research characterising a family of structurally similar but genetically distinct natriuretic peptides, including B-type natriuretic peptide (BNP, formerly named brain natriuretic peptide), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide and urodilatin. ANP and BNP are synthesised by cardiac myocytes (so-called cardiac natriuretic peptides). It is now generally accepted that their release into the blood is increased by factors that raise intra-cardiac pressure and volume overload 4. Unlike ANP, the primary source of BNP is considered to be the cardiac ventricles. Other natriuretic peptides, such as CNP and urodilatin, are not secreted by cardiomyocytes but by other tissues. Cardiac natriuretic peptides are derived from pre-prohormones 4. In particular, BNP is derived from the precursor pre-proBNP, which contains 134 amino acids including a signal peptide of 26 amino acids. The prohormone containing 108 amino acids (proBNP), produced by cleavage of the signal peptide, is further split into BNP, which is considered to be the biologically active hormone, and an inactive amino terminal fragment (NT-proBNP). BNP and NT-proBNP are secreted on an equimolar basis, but their molar ratio in plasma is not 1:1 because BNP has a shorter plasma half-life than NT-proBNP. As indicated, the natriuretic peptide hormones …

N-Terminal pro-B-Type Natriuretic Peptide Concentrations in Mothers just before Delivery, in Cord Blood, and in Newborns

The role of the heart as an endocrine organ was established in 1981 by de Bold et al. (1). Usually, in adults, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted mainly by the cardiac atria and ventricles, respectively (2). Plasma concentrations of these peptides, particularly that of BNP, have been shown to reflect cardiac dysfunction and volume overload in adults and children (3)(4)(5)(6)(7)(8). There is evidence that these peptides have possible roles during fetal life in the regulation of organogenesis of the heart and the cardiovascular system, in the regulation of blood pressure and water balance in the developing embryo, and in the transition from fetal to extra-uterine life (9). BNP may also have …

Plasma A- and B-type natriuretic peptides: physiology, methodology and clinical use.

Time for primary review 25 days. In the 20 years which have passed since the first description by de Bold of a natriuretic and diuretic substance produced in the heart [1], a large body of research has firmly established the position of the heart as an endocrine organ. Two peptides, both containing a 17-amino acid ring structure, have been a focus of much interest: atrial natriuretic peptide (ANP), and brain (or B-type) natriuretic peptide (BNP). A third member of this family of peptides, C-type natriuretic peptide, has been described; it is mainly produced by the endothelium and not by the heart, has no diuretic or natriuretic activity, and will not be discussed here. ANP is produced mainly in the cardiac atria, while BNP, originally isolated from porcine brain, was soon reported to be mainly produced in the cardiac ventricles. In recent years, however, it has become clear that in fact both ANP and BNP are produced both in atria and in ventricles, and that ANP is normally predominant; under pathological conditions production of BNP rises strongly in both atria and ventricles and plasma concentrations may overtake those of (also risen) ANP [2,3]. Both are formed as pre-pro-polypeptides. Pro-atrial natriuretic peptide is a 126-amino acid peptide stored in atrial granulae; upon secretion it is cleaved by a serine protease into equimolar amounts of the active ANP (amino acids 99–126) and the inactive N-terminal fragment N -ANP (amino acids 1–98) [4]. Further degradation of N -ANP may lead to several smaller fragments some of which may also have biological activity [5]. Less is known about the procession of BNP; it is believed to be more constitutively expressed. Pro-brain natriuretic peptide is a 108-amino acid peptide also cleaved into equimolar amounts of the 32-amino acid active BNP and an … * Corresponding author. University Hospital Dijkzigt, Internal Medicine, Rm L-276, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. Tel.: +31-10-463-3764; fax: +31-10-463-4531 boomsma{at}inw1.azr.nl

Past and current perspectives on the natriuretic peptides.

It is now some 15 years since de Bold and colleagues observed the profound hypotension, diuresis, and natriuresis that occurred following injection of acid extracts of cardiac atria into anesthetized rats (1). As is now well documented, these effects were due to a peptide hormone, atrial natri-uretic factor or peptide (ANF or ANP), which is stored in precursor form in atrial specific granules (for review of discovery and early research on ANP see Ref. 2). ANP is a 28-amino acid disulfide bonded peptide that forms the C terminus of a larger precursor, pro-ANP, and which is released into the circulation in response to local wall stretch induced by increased intraatrial volume (3).Following the initial experiments of Sonnenberg and de Bold (l), several atrial natriuretic peptides were purified, sequenced, and chemically synthesized. Administration of pharmacological doses of synthetic ANP confirmed that the peptide was a potent natriuretic substance with mild hypotensive effects (4-7). Infusion of pharmacolo...

Functional properties and dynamics of natriuretic peptide receptors.

Since the discovery of atrial natriuretic factor (ANF or ANP) in 1981 by De Bold et al. (1), more than 6500 articles on the subject have appeared in the literature. For an extensive review on ANP and its receptors, the reader is directed to Reference 2. In this short review, we will consider in a noninclusive manner the dynamics and functional properties of natriuretic peptide receptors. ANP is a 28-amino acid polypeptide hormone secreted mainly by the heart atria in response to atrial stretch that results from an increase in central venous pressure, or systemic and pulmonary hypertension. ANP is a member of a family of natriuretic peptides, which include B-type or brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin. The physiological role of BNP, CNP, and urodilatin remains essentially unknown.The main actions of ANP in the mammalian organism are geared toward the regulation of volumepressure homeostasis (2,3). In the kidney, ANP exerts hemodynamic and tubular actions that l...