Discovery Of Atrial Natriuretic Factor Research Articles

Natriuretic peptides and their receptors

Natriuretic peptides secreted by the heart play a major role in the regulation of cardiovascular homeostasis and remodeling. This minireview series discusses physiological and pathophysiological roles of natriuretic peptides studied in animals and in humans, the structure and signaling mechanism of the receptors mediating peptides’ activities, and the metabolism of natriuretic peptides. The discovery of atrial natriuretic factor (or peptide) (ANP) by de Bold and associates 30 years ago has triggered many later studies, ranging from biochemistry, physiology and genetics to pathophysiology. It is now well established that ANP and the related B-type natriuretic peptide (BNP) play a major role in cardiovascular regulation through their natriuretic, diuretic and vasorelaxant activities, as well as their end-organ activities that suppress cardiac hypertrophy and fibrosis and cardiomyocyte apoptosis. These activities are mediated by the guanylate cyclase (GC)-linked natriuretic peptide receptor-A (NPRA, or GC-A). This ANP/BNP–NPRA signaling system is of major importance in cardiovascular homeostasis, counterbalancing the renin–angiotensin–aldosterone and neurohormonal systems. The physiology and pathophysiology of the ANP/BNP–NPRA system are reviewed here by Kishimoto et al. and by Pandey. The linkage to disease was first demonstrated in transgenic animals, where disruptions of the natriuretic peptide and receptor genes lead to, respectively, salt-sensitive essential hypertension and congestive heart failure accompanied by cardiac hypertrophy and fibrosis. Genetic studies involving very large human populations (as many as 150 000 individuals) have shown that variants within the ANP and BNP genes with reduced levels of circulating peptides are associated with elevated blood pressure - a potent risk factor for heart failure, stroke, myocardial infarction, and other major cardiovascular illnesses. Similar disease associations are found with variants in the receptor genes in humans. Clearly, the ANP/BNP–NPRA system presents an important target in cardiovascular disease therapy. At present, ANP and BNP are used as drugs (carperitide and nesiritide, respectively) for treating breathing difficulty in cases of acutely decompensated heart failure. However, because of their short plasma half-lives (minutes) following intravenous infusion, the effectiveness of these drugs are severely limited. Alternative, modified versions of the peptides are in development, such as chimeric natriuretic peptides with tailored activity profiles, protease-resistant peptides containing amino acid isosters, and peptide–serum albumin fusion proteins. Studies of natriuretic peptide metabolism, as reviewed by Potter, provide valuable guides for designing such peptides. Purification of the NPRA, first achieved from rat lung and bovine adrenal cortex, resulted in copurification of the ANP-binding and GC enzyme activities. Molecular cloning studies utilizing the known sequence homology in the nucleotide cyclase catalytic domains showed that the NPRA and related receptors, including the B-type natriuretic peptide receptor and the guanylin/enterotoxin receptor, constitute a family of GC-linked receptors (receptor-GCs). These receptors, along with receptor protein kinases, belong to the superfamily of enzyme-linked, single-transmembrane segment receptors. The crystal structures of the NPRA extracellular domain dimer with and without bound ANP have been determined (reviewed by Misono et al.). The structures show detailed receptor–ANP binding interactions, and a receptor-bound chloride possibly controlling the receptor allosterically within the renal tubule. The structures also reveal a novel ANP-induced rotation mechanism occurring in the juxtamembrane region that apparently triggers transmembrane signaling. The GC catalytic domain structures of Cyanobacter and green algae GCs recently reported are apparently consistent with the above mechanism. This rotation mechanism of receptor-GC signaling is in contrast with the dimerization (or association) mechanism mediating receptor protein kinase signaling. This minireview series summarizes representative aspects of the advances that have been made in understanding the roles and mechanisms of actions of natriuretic peptides and their receptors. In view of the important role of this regulatory system in cardiovascular physiology and pathophysiology, further advances are eagerly awaited for the betterment of cardiovascular disease therapy.

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 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.

Visualizing the Basis for Paracrine Natriuretic Peptide Signaling in Human Heart

See related article, pages 183–190 Since the discovery of atrial natriuretic factor 25 years ago,1 there has been an explosion of research elucidating the basic biology of endogenous natriuretic peptides. Among other things, this work has established atrial natriuretic factor as one of a family of structurally similar endogenous natriuretic peptides with complex and distinct functional roles in maintaining normal homeostasis and responding to pathological circumstances. The first identified member of this family, atrial natriuretic peptide (ANP), is synthesized and secreted in the cardiac atria under normal conditions and by the ventricular myocardium during fetal development, hypertrophy, or heart failure. BNP, a distinct natriuretic peptide first isolated from the porcine brain, is preferentially synthesized and secreted by ventricular cardiac myocytes and, like ANP, exhibits increased expression during hypertrophy and heart failure. In contrast, C-type natriuretic peptide (CNP) is mainly produced by vascular endothelial cells and neurons, whereas urodilatin is synthesized and secreted by renal cells. The last identified member of this peptide family is dendroaspis natriuretic peptide (DNP), which was first isolated from the venom of the Green Mamba snake.2 Although immunoreactivity to DNP has been identified in several human tissues3 and circulating plasma,4 the gene encoding this natriuretic peptide has not yet been identified within the human genome. Actions of natriuretic peptides are mediated through binding to 3 distinct natriuretic peptide receptors (NPRs) that are located on the cell surface and bind endogenous ligands with varying specificities and affinities (Figure).5 Two of the receptors, NPR-A and NPR-B, have an extracellular (ligand-binding) domain linked to an intracellular (catalytic) domain with guanylate cyclase activity. Consequently, binding to NPR-A and NPR-B triggers increases in guanylate cyclase activity, increased intracellular cGMP, and downstream signaling and responses. The third natriuretic peptide receptor, NPR-C, has no catalytic domain …

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...

A Decade of Atrial Natriuretic Factor Research

The papers that are summarized here and presented in full format in this issue address different aspects of atrial natriuretic factor (ANF) research discussed at the symposium entitled "A Decade of ANF Research" held in Ottawa on June 21–23, 1990. The papers are an excellent reflection of the progress made in basic and clinical research on natriuretic peptides during the time elapsed since the discovery of ANF.

A decade of atrial natriuretic factor research

Present views on the biological significance of atrial natriuretic factor (ANF) relate this polypeptide hormone to the regulation of blood pressure and volume through its modulating effects on renal function, on blood vessel tone and permeability, and on the renin-angiotensin-aldosterone system. Although very important advances in the understanding of ANF have been made over the decade since its discovery, some fundamental facts about ANF biosynthesis and release remain to be elucidated. Stretch-induced enhancement of ANF release appears as the most significant mechanism underlying the endocrine response of the atria to acute volume load. This response decays over a period of minutes, indicating that chronic stimulation of ANF release involves mechanisms different from, or in addition to, those acting during acute stretch-stimulated release. In neither acute nor chronic conditions are the cellular or molecular mechanisms underlying ANF release understood. To better understand long-term stimulation of ANF release, we have conducted extensive in vitro testing of several hormones and neurotransmitters to determine their ability to modify ANF release. From these studies, clear-cut evidence of ANF stimulation was obtained with the vasopressor peptide endothelin. Investigations on the cell and molecular biology of cardiac muscle development and hypertrophy have shown that ANF is involved in cardiac growth. The role played by ANF in these processes is now being determined, but this is one line of evidence that suggests that this hormone, together with other natriuretic peptides, may have autocrine or paracrine functions.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Natriuretic Factor and Hypertension: A Review and Metaanalysis

Atrial natriuretic factor (ANF) is a recently discovered, volume responsive hormone with multiple potent antihypertensive actions. This article reviews data supporting hypothetical associations between ANF and essential hypertension, examines reports of plasma ANF concentrations in hypertension, discusses the efficacy of ANF and its analogs in the treatment of hypertension, and reviews future issues in ANF research. ANF has been shown to elicit vasodilatation, suppress plasma renin activity, inhibit the synthesis and release of aldosterone, antagonize sympathetically-mediated release of norepinephrine, and promote diuresis and natriuresis. A metaanalysis of plasma ANF concentrations reported in normal and hypertensive subjects reveals a 5 +/- 19 pg/mL (pooled, weighted mean and standard deviation) higher ANF level in age-matched, untreated hypertensives without evidence of end-organ damage. This difference may be inappropriately low given the increase in atrial filling pressures found in hypertension. Low doses of ANF elicit greater reductions in blood pressure in hypertensive subjects than in normals. Recently, inhibitors of the ANF-degrading enzyme, neutral endopeptidase, and of the ANF "clearance" receptor have enhanced the antihypertensive actions of endogenous or exogenously administered ANF. Human studies are currently in progress testing the antihypertensive efficacy of orally administered neutral endopeptidase inhibitors. The discovery of ANF has led to the elucidation of a family of natriuretic peptides from brain, heart, and kidney, and promises to enlarge our understanding of volume regulation in normal and pathophysiological states. The possibility that essential hypertension is associated with inappropriately low plasma ANF levels or altered responsiveness to ANF may offer new insights into the pathogenesis and treatment of hypertension.

Discovery of atrial natriuretic factor in the brain: its characterization and cardiovascular implication.

1. We have devised a radioimmunoassay for atrial natriueretic factor (ANF). Its application to rat brain extract led to the discovery of ANF in the brain. In addition to the hypothalamus and the pontine medullary region, it was widely distributed. 2. ANF in the brain is stored in a low molecular weight form, in contrast to pro-ANF in the atria. Thus, the processing of pro-ANF in the bran neuronal cells is different from that in the atria. 3. ANF was found in the anterior and posterior lobes of the pituitary, the peripheral ganglia, adrenergic neurons, and the adrenal medulla. 4. Brain ANF suppressed stimulated dipsogenesis, basal and stimulated vasopressin release, and angiotensin II-stimulated pressor effects. 5. ANF in the peripheral neuronal system inhibits catecholamine synthesis and release. Thus, central ANF functions to reduce the peripheral fluid volume and vascular tone in concert with the peripheral ANF.