Discovery Of Atrial Natriuretic Peptide Research Articles

Synthesis and Significance of Atrial Natriuretic Peptide: A Review

Unhealthy lifestyle habits lead to numerous diseases and among them heart diseases are predominant. Various factors play important role in heart diseases. Amongst such factors is Atrial Natriuretic Peptide (ANP) which tends to be significant. Though the discovery of ANP is the recent one, but its role in diagnosis of cardiovascular disease has taken fasttrack. In this context, authors have tried to review and summarise the current evidences and roles of ANP in cardiovascular diseases along with the focus on rising use of ANP in diagnosis and treatment of cardiovascular diseases. Hence, this is a brief account of discovery and biological actions of ANP, its synthesis and role as a biomarker

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 …

Atrial Natriuretic Peptide - Old But New Therapeutic in Cardiovascular Diseases.

With the discovery of atrial natriuretic peptide (ANP), the heart as an endocrine organ was established. Basic science revealed that ANP, through the particulate guanylyl cyclase A receptor and cGMP, plays a fundamental role in cardiorenal biology. This work has led to the development of ANP as a therapeutic, especially in heart failure (HF). Human genomics has strengthened our understanding of ANP, revealing specific ANP gene variants that may be associated with biological dysfunction, but also may mediate protective properties, including in metabolic syndrome. Advances in understanding the processing and degradation of ANP molecular forms have resulted in therapeutic breakthroughs, especially inhibition of ANP degradation by neprilysin inhibitors. Although ANP is administered intravenously for acute HF, a novel therapeutic strategy is its chronic delivery by subcutaneous injection. An innovative therapeutic development is engineering to develop ANP-based peptides for chronic use. These interconnected topics of ANP biology and therapeutics will be reviewed in detail.

Corin

Natriuretic peptides play a key role in regulation of blood pressure and volume homeostasis due to their natriuretic/diuretic and vasodilatory actions. The natriuretic and diuretic responses to natriuretic peptides are markedly attenuated in edematous disease states. Our goal is to review the mechanisms underlying this phenomenon, with special emphasis on the role of corin in salt retention and edema formation in heart failure and nephrotic syndrome, and pathogenesis of hypertension. Although three decades have passed since the discovery of atrial natriuretic peptide (ANP), major advances in understanding the physiological and pathophysiological role of the natriuretic peptide family in the regulation of sodium (Na) and water balance are still emerging. As well as ANP, the natriuretic peptide family contains at least two other members: brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). Although encoded by different genes, these natriuretic peptides share a high similarity in their chemical structure and biosynthesis pathway. ANP and BNP are produced from proANP and proBNP, respectively, which are converted into the active forms mainly by corin. The latter is a transmembrane serine protease localized to the heart, and to a lesser extent to the kidneys. Recent studies have demonstrated that perturbations in corin activity lead to elevation of the prohormones at the expense of the mature forms, thereby causing the development of salt-sensitive hypertension, preeclampsia, cardiac hypertrophy, and Na and water retention. Natriuretic peptides are an important endocrine system in the regulation of body fluid balance and blood pressure. Corin mediates an essential step in the cascade of natriuretic peptide biosynthesis and eventually their action. Thus, it is postulated that aberrations in the normal activity of corin may contribute to cardiovascular and renal diseases.

The role of atrial natriuretic peptide in modulating cardiac electrophysiology

Since the discovery of atrial natriuretic peptide (ANP) in 1981, significant progress has been made in understanding the mechanism of its release and its role in salt and water balance in the body. It has also become clear that ANP plays a key role in cardiac electrophysiology, modulating the autonomic nervous system and regulating the function of cardiac ion channels. The clinical importance of this role was established when mutations in NPPA, the gene encoding ANP, were identified as a cause of familial atrial fibrillation. This review examines our current understanding of the electrophysiological effects of ANP, and their physiological relationship to clinical studies linking ANP and atrial fibrillation.

From humans to giraffes: The evolution of hypertension and hormones

From humans to giraffes: The evolution of hypertension and hormones

Novel Natriuretic Peptides: New Compounds and New Approaches

The natriuretic peptides (NPs) are a group of structurally similar yet genetically distinct peptides that have diverse actions in cardiovascular, renal, and endocrine homeostasis. Since the discovery of atrial natriuretic peptide in 1981, the diagnostic, prognostic, and therapeutic significance of NPs have been studied extensively in relation to heart failure. Indeed, it now is understood that a hallmark of heart failure is the activation of the cardiac endocrine system, in particular the natriuretic peptide family including atrial natriuretic peptide and B-type natriuretic peptide. Currently, the only approved therapeutic application for NPs is the intravenous treatment of acute decompensated heart failure. However, in recent years there has been considerable research aimed at creating novel NPs and administering them via novel routes. This review focuses on the novel NPs that have been created and on novel approaches for their administration.

Roles of atrial natriuretic peptide and its therapeutic use

Since the discovery of atrial natriuretic peptide (ANP), there has been tremendous progress in our understanding of the physiologic and pathophysiologic, diagnostic, and therapeutic roles of ANP. The diagnostic application of ANP and brain natriuretic peptide (BNP) has been reviewed by many investigators, and meta-analyses of therapeutic use of BNP were reported from the USA. However, there are few reviews concerning the therapeutic use of ANP in patients with various conditions. Therefore, this review focuses on the recent clinical evidence of ANP in therapeutic use and experimental data that rationally support the therapeutic use of ANP.

Natriuretic Peptides: New Players in Energy Homeostasis

In this issue of Diabetes , Miyashita et al. (1) provide compelling new evidence that natriuretic peptides (NPs) play a key role in the regulation of body weight and energy metabolism. In a series of complementary experiments, the investigators show that the NP–cyclic guanosine monophosphate (cGMP) signaling system increases the capacity for fat oxidation, activates mitochondrial biogenesis, and prevents the deleterious effects of a high-fat diet (HFD). NPs are not new players in metabolic regulation. Since the discovery of atrial natriuretic peptide (ANP) in 1980 (2), a large body of work has highlighted the multifaceted roles of NPs in the regulation of blood volume and arterial pressure. NPs are members of a family of structurally similar but genetically distinct endogenous peptide hormones. The NP family consists of at least three mammalian peptides: atrial-, brain-, and C-type (ANP, BNP, and CNP, respectively) (3). ANP and BNP preferentially bind to a particulate guanylyl cyclase (GC) receptor called GC-A, whereas CNP is the physiological ligand for GC-B (4). Through their diuretic, vasodilatory, and antimitogenic properties, the NPs play an important role in the regulation of cardiovascular, renal, and endocrine homeostasis (3–5). New findings by Miyashita et al. convincingly demonstrate that the NP-cGMP system also plays a role in the regulation of fatty acid metabolism and body weight regulation (Fig. 1). The researchers generated a series of mouse models to investigate. BNP transgenic mice, which overexpress BNP in the liver at supraphysiological levels (>100-fold compared with resting level), tended to be leaner than wild-type mice. When challenged with HFD, these mice resisted diet-induced obesity and insulin resistance. They had lower total body fat, increased whole-body oxygen consumption and fat …

Therapeutic potential of infused cardiac natriuretic peptides in myocardial infarction

After the pivotal discovery of atrial natriuretic peptide (ANP) in 1981 and subsequent identification of BNP in 1988, the focus of worldwide research on cardiac peptides (NP) has moved over...

B-type natriuretic peptide: beyond a diagnostic.

The concept of the heart as an endocrine organ has been attractive since the discovery of atrial natriuretic peptide. This review focuses on the second discovered natriuretic peptide from the heart - B-type natriuretic peptide (BNP), widely used as a tool in the diagnosis of heart failure (HF). Controversy remains regarding its use as a therapeutic agent in HF. This article places into perspective some of the debate and provides insights into the therapeutics of BNP and the importance of its second messenger 3'5' cyclic guanosine monophosphate, which also is the second messenger for nitric oxide and is modulated by renal phosphodiesterases.

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 …

Mechanisms of atrial natriuretic peptide secretion from the atrium

Since the discovery of atrial natriuretic peptide (ANP) more than 20 years ago, numerous studies have focused on the mechanisms regulating ANP secretion. From a physiological standpoint, the most important factor governing ANP secretion is mechanical stretching of the atria, which normally occurs when extracellular fluid volume or blood volume is elevated. In addition, the ability of several vasoconstrictors to increase ANP secretion can be traced to their indirect effects on atrial stretch via increases in cardiac preload or afterload. Whether vasoconstrictors such as angiotensin II and vasopressin have a direct positive or negative effect on ANP secretion has not been determined with certainty. Two paracrine factors derived from endothelial cells play important roles in modulating ANP secretion. Endothelin, a potent vasoconstrictor, stimulates ANP secretion and augments stretch induced ANP secretion. The dramatic increase in ANP release produced by cardiac ischemia appears to be mediated in part by endothelin. Nitric oxide (NO), an important vasodilator, is also produced by endothelial cells and inhibits ANP secretion acting through cyclic GMP as an intracellular messenger. Several recent studies have helped to define the cellular mechanism contributing to regulation of ANP secretion including stretch-activated ion channels, prostaglandins, cytochrome P450, G proteins and cell calcium. A number of steps in the cellular transduction of the ANP signal remain to be resolved. The release of ANP in disease states such as myocardial infarction and heart failure appears to be related to both mechanical and cellular events.

Cardiac and intestinal natriuretic peptides: Insights from genetically modified mice

Since the original discovery of atrial natriuretic peptide (ANP) more than two decades ago, the application of gene targeting technology in mice has provided new insights into the diverse physiological functions of natriuretic peptides and their membrane guanylyl cyclase (GC) receptors. Disruption of the genes for ANP or its receptor, GC-A, demonstrated that this system is not only essential for the maintenance of normal blood pressure and volume, but in addition exerts local antihypertrophic effects in the heart. Disruption of the genes encoding B-type (BNP) or C-type natriuretic peptides (CNP) or the CNP-receptor, GC-B, demonstrated that these “natriuretic” peptides are in fact unlikely to physiologically regulate renal sodium excretion but instead exert important autocrine/paracrine cGMP-mediated effects on cellular proliferation and differentiation in various tissues. Notably, the intestinal peptide uroguanylin, which activates a third guanylyl cyclase receptor (GC-C), exerts diuretic/natriuretic activity and links the intestine and kidney in an endocrine way to modulate renal function in response to oral salt load. Reviewed here is the physiology of cardiac and intestinal natriuretic peptides and their guanylyl cyclase receptors, with special focus on the information gained to date from genetically modified mice.

Modulation of the natriuretic peptide system in heart failure: from bench to bedside?

Since the discovery of atrial natriuretic peptide, the unravelling of the natriuretic peptide system has been a story of scientific success. However, bridging the gap between bench and bedside has proved difficult, and as yet has not provided any major clinical progress. In this review we will first give a detailed outline of the key elements constituting the natriuretic peptide system. Secondly, we will briefly explain the underlying rationale, basic concepts and evidence behind currently pursued strategies to potentiate the natriuretic peptide system. Thirdly, we will highlight some of the problems that have so far hindered successful translation of these theoretically viable treatment options into tangible clinical progress.

Role of Cardiac Natriuretic Peptide Testing in Heart Failure

The long-predicted natriuretic and endocrine function of the heart was demonstrated more than 20 years ago (1) by the discovery of atrial natriuretic peptide [atrial natriuretic factor, A-type natriuretic peptide (ANP)]. This led to the description of a family of structurally similar but genetically distinct peptides, constituting the natriuretic peptide (NP) family, which contribute to the maintenance of cardiovascular homeostasis. These looped peptides are the naturally occurring antagonists of the renin-angiotensin-aldosterone system and of the sympathetic nervous system. They promote natriuresis and diuresis, act as vasodilators, and exert antimitogenic effects on cardiovascular tissues. Two members of the NP family, ANP and brain natriuretic peptide [B-type natriuretic peptide (BNP)] are secreted by the hemodynamically stressed heart mainly in response to myocardial stretch induced by volume load. ANP and BNP appear to form a dual, integrated NP system with ANP acting as a rapid-response hormone and BNP as a backup hormone activated only after prolonged ventricular overload. The NP system is activated to its highest degree in ventricular dysfunction and has an important role in maintaining the compensated state of asymptomatic heart failure (HF) and delaying disease progression. The increased plasma ANP and BNP seen in HF patients is not unique: NPs are increased in all patients with edematous disorders, such as renal failure or ascitic liver cirrhosis, that lead to increased atrial tension or central blood volume (2). The NPs are synthesized as preprohormones. The endocrinologically active C-terminal peptides (ANP and BNP) and their N-terminal prohormone fragments are found in plasma. It is uncertain at present whether the proteolytic cleavage of proBNP to N-terminal proBNP (NT-proBNP) 1–76 and BNP (C-terminal 32 amino acids) occurs at the time of secretion or later in the circulation (3). ProBNP is, however, a substrate of the transmembrane serine protease corin, suggesting that proBNP is …

The impact of cardiac natriuretic peptide determination on the diagnosis and management of heart failure.

The long-predicted endocrine function of the heart has been proven by the discovery of atrial natriuretic peptide (atrial natriuretic factor, A-type natriuretic peptide; ANP) 20 years ago. This subsequently led to the description of a whole family of structurally similar but genetically distinct peptides, the natriuretic peptide family, which contributes to cardiovascular homeostasis. These looped peptides promote natriuresis and diuresis, act as vasodilators, and exert antimitogenic effects on cardiovascular tissues. Two members, ANP and brain natriuretic peptide (B-type natriuretic peptide; BNP) are secreted by the heart mainly in response to myocardial stretch induced by volume load. The natriuretic peptides are synthesized as preprohormones. The C-terminal endocrinological active peptides (ANP, BNP) and their N-terminal prohormone fragments are found in plasma. The natriuretic peptide system is activated to its highest degree in ventricular dysfunction. However, natriuretic peptides are increased in all patients with edematous disorders which lead to an increase in atrial tension or central blood volume, such as renal failure or ascitic liver cirrhosis. It could be demonstrated that in chronic heart failure patients and during the subacute phase of myocardial infarction, of all tested neurohormones, the cardiac natriuretic peptides were best markers to identify heart failure and the most powerful predictors of morbidity and mortality. Natriuretic peptides are independent markers for risk assessment. In comparative studies BNP was superior to ANP and its N-terminal prohormone fragments in myocardial infarction as well as in chronic heart failure patients. Less data on N-terminal proBNP (NT-proBNP) is available, but BNP and NT-proBNP appear to be equivalent markers. For primary care physicians natriuretic peptide measurement is useful to decide which patient with suspected heart failure warrants further investigation, particularly when assessment of left ventricular function is not readily available. Natriuretic peptides have an excellent negative predictive value, particularly in high risk patients. An increase in BNP is serious enough to warrant follow-up examinations. For the cardiologists the natriuretic peptides are helpful for guidance of therapy and monitoring disease course in heart failure patients and for risk stratification in heart failure and myocardial infarction.

Regulation of the atrial natriuretic peptide receptor guanylyl cyclase.

The discovery of atrial natriuretic peptide (ANP) and the demonstration that its receptors were coupled to the activation of particulpate guanylyl cyclase (GC) and that ANP receptors copurified with GC activity were important findings in the 1980s. With the molecular cloning of the ANP receptor, the knowledge gained of its structure has allowed new questions to be posed about how signaling through this receptor is regulated-and about signaling through a growing family of related receptors having intrinsic GC activity (1). Here, I review experiments addressing the role of the protein kinase-like domain of the ANP receptor, the regulation of receptor function by adenine nucleotides, the role of dimerization in receptor activation, and the identification of a novel protein-serine phos-phatase that may mediate desensitization of the ANP receptor.

Possible modulatory roles of natriuretic peptide systems in the progression of renal disorders

Since the original discovery of atrial natriuretic peptide (ANP) more than two decades ago, the application of gene targeting technology in mice has provided new insights into the diverse physiological functions of natriuretic peptides and their membrane guanylyl cyclase (GC) receptors. Disruption of the genes for ANP or its receptor, GC-A, demonstrated that this system is not only essential for the maintenance of normal blood pressure and volume, but in addition exerts local antihypertrophic effects in the heart. Disruption of the genes encoding B-type (BNP) or C-type natriuretic peptides (CNP) or the CNP-receptor, GC-B, demonstrated that these “natriuretic” peptides are in fact unlikely to physiologically regulate renal sodium excretion but instead exert important autocrine/paracrine cGMP-mediated effects on cellular proliferation and differentiation in various tissues. Notably, the intestinal peptide uroguanylin, which activates a third guanylyl cyclase receptor (GC-C), exerts diuretic/natriuretic activity and links the intestine and kidney in an endocrine way to modulate renal function in response to oral salt load. Reviewed here is the physiology of cardiac and intestinal natriuretic peptides and their guanylyl cyclase receptors, with special focus on the information gained to date from genetically modified mice.

Natriuretic Hormone: A Contribution to the Development of a Hypothesis

For two decades before the discovery of atrial natriuretic peptide and the recent announcement of the isolation of endogenous ouabain, the experimental background for the hypothesis of the existence of a natriuretic hormone, mostly furnished by a few laboratories, kept this challenge alive.