Brain and other natriuretic peptides: molecular aspects

Transcription

1 The European Journal of Heart Failure 6 (2004) Brain and other natriuretic peptides: molecular aspects Marc Vanderheyden*, Jozef Bartunek, Marc Goethals Cardiovascular Center, Onze Lieve Vrouwziekenhuis, Moorselbaan 164, 9400 Aalst, Belgium Abstract Received 23 December 2003; accepted 13 January 2004 Natriuretic peptides have emerged as important candidates for development of diagnostic tools and therapeutic agents in cardiovascular disease. The family contains of three major peptides ANP, BNP, CNP that participate in cardiovascular and cardiorenal homeostasis. Each of these natriuretic peptides binds differentially to specific receptors that signal through different mechanisms. They are cleared enzymatically by neutral endopeptidase as well as by receptor-mediated endocytosis. Because of its fast induction and specific expression in overt heart failure, BNP seems the most promising natriuretic peptide. It is predominantly synthesized in the cardiac ventricles, released as pre-probnp and then enzymatically cleaved to BNP and the N- terminal portion of BNP(NT-proBNP). Blood measurements of BNP and NT-proBNP have been shown to identify patients with LV dysfunction. This review focuses on the physiology of natriuretic peptides as a group and brain natriuretic peptide in more detail, its structure and regulation as well as its effects at the cellular level European Society of Cardiology. Published by Elsevier B.V. All rights reserved. Keywords: 1. Introduction Natriuretic peptides; Heart failure Though it is well known that neurohormones are activated and released into the circulation in patients with heart failure, the therapeutic importance of this observation has only emerged in the past years. To counter-balance the effects of vasoconstrictor-mitogenic-sodium-retaining neurohormones, released by the sympathetic nervous system and the RAAS, and to maintain circulatory homeostasis the body produces a family of vasodilator antiproliferative natriuretic peptides that have an important role in heart failure both as counter-regulatory hormones and as potential exogenous therapy. In 1981 de Bold and colleagues observed that extracts of atrial tissue infused into rats caused a copious diuresis w1x. Subsequent isolation and purification quickly revealed that a new peptide called atrial natriuretic peptide was the mediator of this diuretic response w1x. Ten years following the description of atrial natriuretic peptide, a second compound of the family of natriuretic *Corresponding author. Tel.: q ; fax: q address: marc.vanderheyden@olvz-aalst.be (M. Vanderheyden). peptides was described. This was called brain natriuretic peptide because of it first isolation from porcine brain w2x. Over the past decade, it has been demonstrated that this peptide has great pathophysiological importance in diagnosing heart failure w3,4x as well as in risk stratification and guiding heart failure therapy w5x. This review focuses on natriuretic peptides as a group and brain natriuretic peptide in more detail, its structure and regulation as well as its effects at the cellular level. 2. The natriuretic peptide family Four distinct natriuretic peptides have been described (Table 1). They all have a characteristic 17 amino-acid residue ring structure formed by an intramolecular disulfide bridge between two cysteine residues w6x. The amino- and carboxyl terminal tails varies between the different peptides leading to polypeptides of 28 amino acids (ANP), 32 amino acids (BNP), 53 amino acids (CNP) and 38 amino acids for D-type w7x. They all also exist as a pro-hormone with a relatively high molecular weight that is cleaved before release into the circulation w8x. The ANP and BNP precursor peptide genes reside in tandem on the distal short arm of chromosome /04/$ - see front matter 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. doi: /j.ejheart

2 Table 1 Characteristics of the natriuretic peptides ANP BNP CNP DNP BNP NT-proBNP Human chromosomal 1p36.2 1p36.2 1p unk location Components Ct-ANP(28 AA) BNP(32 AA) Nt fragment (1 76) CNP-22 DNP-like peptide Nt-ANPt (98 AA) NT-proBNP (1 108) CNP-53 in humans Hormonally active endocrineyparacrine endocrineyparacrine paracrine unk Genesis Cleavage from pro-anp Cleavage form pro-bnp Release from Cleavage from pro-cnp unk ventricular myocytes Half-life 20 min 120 min Clearance mechanism Neutral endopeptidase Neutral endopeptidase Renal clearance Neutral unk endopeptidase Clearance receptor Clearance receptor Clearance receptor NPR-C NPR-C NPR-C Approved cutoff for CHF unk 100 pgyml Age-75 years: 125 pgyml diagnosis Age)75 years: 450 pgyml Tissue distribution Cardiac atria Brain Brain Brain, ovary, uterus Snake venom and ventricles Cardiac ventricles Cardiac ventricles Testis epidydimis Principal phenotype Salt-sensitive Myocardial fibrosis Myocardial fibrosis Dwarfism unk of knockout mice Hypertension Early death Ct means carboxy-terminal, Nt amino-terminal, AA aminoacid and unk unknown. 262 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) Downloaded from at Pennsylvania State University on February 23, 2013

3 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) w9xwhereas the CNP precursor peptide gene is localized on chromosome 2 w9x. The gene encoding DNP has not been cloned w10x Atrial natriuretic peptide The messenger RNA transcript for atrial natriuretic peptide is approximately 1 kb in size and encodes a precursor protein (pro-atrial natriuretic peptide) of 126 amino acids. Human pro-atrial natriuretic peptide is proteolytically cleaved to a 98-amino-acid amino-terminal fragment and a 28-amino-acid carboxy-terminal fragment that represents biologically active ANP w11x. Both fragments as well as other fragments of the aminoterminal molecule circulate in plasma. Several data suggest that these pro-anp fragments may be as or even more important than ANP as a natriuretic hormone w12x. Atrial natriuretic peptide is present in the ventricular tissue of fetuses and neonates, in hypertrophied ventricles as well as in low concentrations in normal ventricles. However, the atria are the main source in the adult normal heart w7x. A separate natriuretic 32-amino-acid peptide pro-anp fragment called urodilatin has been identified in human urine w13x. Plasma levels of urodilatin are negligible since it is produced within the kidney by a unique processing pathway. Distal nephron cells have been shown to secrete an ANP pro-hormone that could be the precursor of urodilatin. Urodilatin appears to be more resistant to neutral endopeptidases (NEP). Its role in heart failure, if any, is still not very clear w14x Brain natriuretic peptide Human BNP is encoded by a single copy gene consisting of three exons and two introns. Its mrna has a characteristic feature by virtue of the presence of four AUUUAA repeat sequences within the 39 untranslated region that is considered to produce mrna stability w8x. The post-translational processing of the BNP precursor gene is different from that of the human ANP precursor. Regulation of ANP seems to occur at the level of release from storage granules whereas BNP regulation takes place during gene expression w15x. Human brain natriuretic peptide is produced in bursts in the heart as 108 amino acid precursor (pro-bnp) w16x. Further processing releases a mature biologically active 32-amino-acid molecule BNP, which corresponds to the C-terminal sequence of the human BNP precursor and a 76 aminoacid N-terminal fragment (NT-proBNP)(Fig. 1) w17x. The biologically active BNP, the intact 108 amino acid probnp and the remaining part of the prohormone NT-proBNP all circulate in the plasma and can be measured by immunoassay. Circulating BNP consists of 32 amino acids with a characteristic ring closed by a Fig. 1. Structure of brain natriuretic peptide and its activation site. disulfide bond between two cysteine residues, an aminoterminal tail of nine amino acids, and a carboxylterminal tail of six amino-acids w8x. Although atrial and to a greater extent ventricular cardiomyocytes constitute the major source of BNP related peptides, recent data demonstrated that other cells such as cardiac fibroblasts can also produce BNP. In addition, various neurohormones may stimulate cardiac BNP production in interplay between different cardiac cell types. In normal subjects the plasma concentrations of NTproBNP and BNP are similar. Both are continuously released from the heart and are detectable at picomolar concentrations in the venous blood of healthy subjects. With a half life of approximately 22 min in blood w8x, BNP can accurately reflect pulmonary capillary wedge pressure changes every 2 h. The plasma half-life of NTproBNP is 120 min suggesting that meaningful changes in hemodynamics could be reflected by this test approximately every 12 h w18x. However, in patients with left ventricular dysfunction NT-proBNP levels rise more than BNP with plasma concentration 2 10 times higher than BNP. The exact mechanism responsible for this relative change in peptide levels remains undetermined. Shifts in cardiac secretion andyor clearance mechanisms are thought to play a role. Taken together the greater rise in NT-proBNP during heart failure may make it a better marker as compared to BNP w19x. The correlation between BNP and estimated glomerular filtration rate is approximately rsy0.20. This implies a higher cutoff for BNP in the diagnosis of CHF when kidney disease advances. Nevertheless using this approach, BNP maintains a high level of diagnostic utility w20x. NT-proBNP has a stronger correlation with egfr of approximately rsy0.60, and is influenced by the normal age-related decline in renal function. Therefore, below an egfr of 60 mlyminy1.73 m, which is 2 common in the elderly, the cutoff of NT-proBNP for detecting CHF might be less accurate w21x. This tight relationship to renal function has led some investigators to suggest that NT-proBNP reflects cardiorenal instead of cardiac function w18x.

4 264 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) C-type natriuretic peptide A third natriuretic peptide, C-type NP is expressed primarily in the central nervous system and vascular tissues and, unlike ANP and BNP, is nearly non-existent in cardiac tissue w22x. The gene encoding CNP is localized to human chromosome 2 and contains two exons separated by an intron. The NPCC gene encodes a 126-residu CNP precursor peptide pro-cnp that is processed to generate 22- (CNP-22) and 53-amino acid peptides (CNP-53). CNP-22 is more widely and abundantly expressed and is more potent than C-53 peptide w7x. CNP has remarkable similarity to ANP in its amino acid sequence but lacks the Carboxy-terminal tail of ANP w23x. The low almost undetectable levels of CNP suggests that this peptide acts primarily as a neurotransmitter in a paracrine way w24x, while ANP and BNP function more as true counter-regulatory hormones w25x. Nevertheless, CNP does play an important role in cardiovascular physiology as a potent vasorelaxant, as well as an inhibitor of vascular smooth muscle proliferation and endothelial cell migration w17x. Recent data also reported a lusitropic and negative inotropic effect of CNP infusion in isolated papillary muscle w26x D-type natriuretic peptide Dendroaspis natriuretic peptide (DNP), a 38-aminoacid peptide is the newest of the natriuretic peptides. It was isolated from the venom of the Green Mamba (Dendroaspis angusticeps) and has structural similarities to the three known human cardiac natriuretic peptides w27x, It shares the characteristic 17-aminoacid disulfide ring with all natriuretic peptides but is structurally different in its N- and C-terminal regions. Human data about this NP are scarce: The gene for DNP has not been cloned neither in the snake nor in any mammal in contrast to the other natriuretic peptides. Recently, a DNP-like peptide has been isolated from human plasma and human atria, yet conclusive evidence about its presence in man remains controversial. Some authors suggest DNP is a primitive, ancestral cardiac natriuretic peptide, an evolutionary precursor to ANP and BNP w10x. 3. Natriuretic peptide receptors The natriuretic peptides are ligands for three different cell surface receptors named natriuretic peptide receptor (NPR) A, NPR-B and NPR-C that mediate their physiological effects. Each of these receptors contains a single transmembrane domain and an extracellular binding domain w28x. Natriuretic peptide receptor A and B are structurally similar, with approximately 44% homology in the ligand-binding extracellular domain w29x. Although both receptors are found in the adrenal gland and the kidney, NPR-A is most abundant in large blood vessels in contrast to NPR-B that predominates in the brain, particularly in the pituitary gland w8x. ANP and BNP bind preferentially to NPR-A that dimerizes and uses a chloride ion to hold itself in the open position. The receptor is linked to a cyclic guanylate monophosphate (c-gmp)-dependent signaling cascade that mediates most of its biological activity w24x. Mice lacking this functional NPR-A receptor exhibit hypertension, cardiac hypertrophy and dilatation and die suddenly before the age of 6 months w30x. The relatively low affinity of BNP for NPR-A with a potency approximately 10-fold lower than that of ANP w31x, has led to the speculation that an additional BNPspecific guanylate cyclase receptor might play a role w26x. Of note in NPR-A knockout mice testis and adrenal glands retain significant high-affinity response to BNP that can only be accounted for by the presence of a novel receptor in these tissues that prefers BNP over ANP. Although the physiological significance and the biochemical components of this receptor remains to be established, its existence does reinforce the notion that ANP and BNP are likely to carry out at least some independent actions w26x. CNP does not act through NPR-A but selectively activates NPR-B a second guanylate cyclase receptor w26x. As previously mentioned, this receptor is similar to NPR-A. Nevertheless, it is only weakly sensitive to ANP and BNP w24x. In contrast to NPR-A and NPR-B the NPR-C is devoid of guanyl cyclase activity and contains 37 amino acid cytoplasmatic domain that contains a G proteinactivating sequence w24x. They are the most widely and abundantly expressed natriuretic peptide receptors and are located in several tissues including vascular endothelium, smooth muscle, heart, adrenal glands and kidney w32x. As demonstrated by studies performed in NPR-C knockout mice, it serves as a clearance receptor for ANP, BNP and CNP w33x. All three natriuretic peptides bind to this receptor in the order of ANP) CNP)BNP w34x, are internalized and enzymatically degraded, after which the C-receptor returns to the cell surface w7x. In addition, recent data indicate that the NPR-C alters target cell function through Gi proteincoupled inhibition of membrane adenylate cyclase activity w24x. The lower affinity of NPR-C for BNP with an interaction partly accounts for the longer plasma halflife of BNP as compared to ANP in man w24x. 4. Clearance of natriuretic peptides Although the rate of synthesis and release of natriuretic peptides is a major regulator of plasma concentrations, the rate of removal of the peptides from the

5 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) Fig. 2. Action of natriuretic peptides at target cells. GC means guanyl cyclase, NPR-A natriuretic peptide receptor A, NPR-B natriuretic peptide receptor B, NPR-C natriuretic peptide receptor C, NEP neutral endopeptidase, aldo aldosterone, OSorthosympathetic system. circulation is also important w35x. The clearance involves two main pathways: enzymatic degradation by neutral endopeptidase and as previously mentioned receptormediated endocytosis followed by lysosomal degradation via the natriuretic peptide receptor C (or clearance receptor) (Fig. 2) w6x. Renal clearance plays a lesser role at least for active C-terminal peptides. NEP, a zinc metallopeptidase is widely distributed on the surface of endothelial cells, smooth-muscle cells, cardiac myocytes and fibroblasts and is particularly concentrated at the brush border membranes in the proximal tubule of the kidney w17x. It cleaves the natriuretic peptides and opens the ring structure, thus inactivating the peptides w8x. The NPR-C is the most widely and abundantly expressed natriuretic peptide receptor and is located in several tissues including vascular endothelium and smooth muscle, heart, adrenal gland and kidney w11,24x. NPR-C knockout mice are characterized by a prolonged halflife of exogenous ANP, mild reductions in blood pressure, increased basal bone turnover and bone deformities w33x. The relative importance of these two mechanisms in the clearance is controversial. Although data from a number of studies in normal animals have demonstrated that NPR-C blockade has a greater effect on ANP clearance than do NEP inhibitors, others have demonstrated that the enzymatic and receptor clearance pathways equally contribute to the degradation of ANP and BNP at physiological plasma concentrations. In addition, it has been demonstrated that in states of chronically elevated endogenous natriuretic peptides, such as occurs in chronic heart failure, the clearance receptor may play a lesser role than NEP in the metabolism of the peptides because of higher receptor occupancy and species dependent ANP-mediated down-regulation of the NPR- C w36x. 5. Regulation and induction of ANP and BNP At the cellular level, stretch is the predominant stimulus controlling the release of BNP from the atria and the ventricles. The increased wall stretch acts directly or via local paracrine factors such as endothelin-1 w37x, nitric oxide w17x, and angiotensin II w38x. Apart from myocyte stretch other stimuli such as tachycardia w39x and glucocorticoids w40x contribute to the induction of cardiac BNP mrna in overt heart failure w17x.

6 266 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) ANP is primarily released by increased atrial transmural pressure. The release of BNP is modulated by both pressure and volume overload as evidenced by the correlation between left-ventricular chamber size w41x, left ventricular enddiastolic pressure w42xand plasma BNP concentration. Note, in vivo data demonstrated a slow ANP gene induction within days after the initiation of increased cardiac overload. In contrast there is a rapid within hours activation of the BNP gene, whenever wall stretch increases w43x. The slow induction of ANP allows storage of ANP in granules and periodical release from ANP out of these granules w44x. Because of the high turnover of the BNP messenger RNA, BNP cannot be stored but is released in bursts w45x. Experimental data suggest that upregulation of cardiac ANP is less dependent on the severity of heart failure; Indeed ANP mrna is already induced in compensated heart failure when hypertrophy is present but LVEDP is still normal. In contrast BNP mrna is only induced in heart failure when LVEDP is elevated w46x. Taken together these data not only give rise to the concept of BNP as an emergency hormone but also point toward the role of BNP as a marker for diagnosing the transition from compensated to decompensated heart failure w47x. 6. Actions of the natriuretic peptides 6.1. Renal effects At the level of the kidney, natriuretic peptides have multiple actions including stimulating natriuresis and diuresis. Atrial as well as brain natriuretic peptide exert their effects on the kidney primarily at the level of the glomerulus and collecting duct. In the glomerulus, it causes afferent arteriolar dilation together with efferent arteriolar vasoconstriction, thereby increasing the glomerular filtration rate w48x. In the collecting duct, it decreases sodium reabsorption, thereby increasing sodium excretion w49x. Both also inhibit the secretion of renin, angiotensin II and aldosterone w50x. Finally, mice over-expressing the BNP gene have a lower degree of glomerular hypertrophy and mesangial expansion with intraglomerular cells than wild mice in response to renal ablation w51x Cardiovascular effects Transgenic mice that overexpress BNP have a lower blood pressure and a lower peripheral vascular resistance than wild types w51x. This is chiefly caused by a primary shift of intravascular fluid into the extravascular compartment and an increase in venous capacitance with subsequent rise in natriuresis, resulting in a reduction of preload w20x. However, mice with targeted disruption of BNP develop multifocal fibrotic lesions in the cardiac ventricle in the absence of systemic hypertension or ventricular hypertrophy w52x. These observations together with the lusitropic effects of BNP infusion suggest BNP acts as a cardiomyocyte-derived antifibrotic factor in vivo that may function as a local regulator of ventricular remodeling w24x. Atrial as well as brain natriuretic peptides also have important central and peripheral sympathoinhibitory effects w7x. Damping of the baroreceptors, suppressed release of catecholamines from autonomic nerve findings and especially suppression of sympathetic outflow from the central nervous system all have been reported w17x. Finally, the activation threshold of vagal afferents is lowered thereby suppressing the reflex tachycardia and vasoconstriction that accompanies the reduction in preload w53x. 7. Conclusion The natriuretic peptide family plays a distinct physiological and pathophysiological role in cardiovascular control. It consists of at least four ligands, ANP, BNP, CNP DNP and three types of receptors expressed in target tissues with tissue specificity. By binding to all three classes of receptors the natriuretic peptides act in concert to regulate cardiovascular function. Because of its fast induction and specific expression in overt heart failure, BNP seems the most promising natriuretic peptide as a marker of LV dysfunction and makes it an important component of future cardiac care. References w1x de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci 1981;28: w2x Sudoh T, Minamino N, Kangawa K, Matsuo H. Brain natriuretic peptide-32: N-terminal six amino acid extended form of brain natriuretic peptide identified in porcine brain. Biochem Biophys Res Commun 1988;155: w3x Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37: w4x McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from breathing not properly (BNP) multinational study. Circulation 2002;106: w5x Cheng V, Kazanagra R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37: w6x Nakao K, Ogawa Y, Suga S, Imura H. Molecular biology and biochemistry of the natriuretic peptide system. II: Natriuretic peptide receptors. J Hypertens 1992;10: w7x Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998;339: w8x Valli N, Gobinet A, Bordenave L. Review of 10 years of the clinical use of brain natriuretic peptide in cardiology. J Lab Clin Med 1999;134: w9x Tamura N, Ogawa Y, Yasoda A, Itoh H, Saito Y, Nakao K. Two cardiac natriuretic peptide genes (atrial natriuretic peptide

7 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) and brain natriuretic peptide) are organized in tandem in the mouse and human genomes. J Mol Cell Cardiol 1996;28: w10x Richards AM, Lainchbury JG, Nicholls MG, Cameron AV, Yandle TG. Dendroaspis natriuretic peptide: endogenous or dubious? Lancet 2002;359:5 6. w11x Espiner EA, Richards AM, Yandle TG, Nicholls MG. Natriuretic hormones. Endocrinol Metab Clin North Am 1995;24: w12x Vesely DL, Douglass MA, Dietz JR, et al. Three peptides from the atrial natriuretic factor prohormone amino terminus lower blood pressure and produce diuresis, natriuresis, andyor kaliuresis in humans. Circulation 1994;90: w13x Schulz-Knappe P, Forssmann K, Herbst F, Hock D, Pipkorn R, Forssmann WG. Isolation and structural analysis of urodilatin, a new peptide of the cardiodilatin-(anp)-family, extracted from human urine. Klin Wochenschr 1988;66: w14x Ritter D, Chao J, Needleman P, Tetens E, Greenwald JE. Localization, synthetic regulation, and biology of renal atriopeptin-like prohormone. Am J Physiol 1992;263:F503 F509. w15x Onuoha GN, Nicholls DP, Patterson A, Beringer T. Neuropeptide secretion in exercise. Neuropeptides 1998;32: w16x Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90: w17x de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362: w18x McCullough PA, Omland T, Maisel AS. B-type natriuretic peptides: a diagnostic breakthrough for clinicians. Rev Cardiovasc Med 2003;4: w19x Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol (Oxf) 1997;47: w20x Vesely DL. Natriuretic peptides and acute renal failure. Am J Physiol Renal Physiol 2003;285:F167 F177. w21x McCullough PA, Sandberg KR. B-type natriuretic peptide and renal disease. Heart Fail Rev 2003;8: w22x Sudoh T, Minamino N, Kangawa K, Matsuo H. C-type natriuretic peptide (CNP): a new member of natriuretic peptide family identified in porcine brain. Biochem Biophys Res Commun 1990;168: w23x Tawaragi Y, Fuchimura K, Tanaka S, Minamino N, Kangawa K, Matsuo H. Gene and precursor structures of human C-type natriuretic peptide. Biochem Biophys Res Commun 1991;175: w24x Kone BC. Molecular biology of natriuretic peptides and nitric oxide synthases. Cardiovasc Res 2001;51: w25x Barr CS, Rhodes P, Struthers AD. C-type natriuretic peptide. Peptides 1996;17: w26x Goy MF, Oliver PM, Purdy KE, et al. Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide. Biochem J 2001;358: w27x Schweitz H, Vigne P, Moinier D, Frelin C, Lazdunski M. A new member of the natriuretic peptide family is present in the venom of the green mamba (Dendroaspis angusticeps). J Biol Chem 1992;267: w28x Porter JG, Arfsten A, Fuller F, Miller JA, Gregory LC, Lewicki JA. Isolation and functional expression of the human atrial natriuretic peptide clearance receptor cdna. Biochem Biophys Res Commun 1990;171: w29x Koller KJ, Goeddel DV. Molecular biology of the natriuretic peptides and their receptors. Circulation 1992;86: w30x Pandey KN, Oliver PM, Maeda N, Smithies O. Hypertension associated with decreased testosterone levels in natriuretic peptide receptor-a gene-knockout and gene-duplicated mutant mouse models. Endocrinology 1999;140: w31x Schulz S, Singh S, Bellet RA, et al. The primary structure of a plasma membrane guanylate cyclase demonstrates diversity within this new receptor family. Cell 1989;58: w32x Maack T, Suzuki M, Almeida FA, et al. Physiological role of silent receptors of atrial natriuretic factor. Science 1987;238: w33x Matsukawa N, Grzesik WJ, Takahashi N, et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc Natl Acad Sci USA 1999;96: w34x Suga S, Nakao K, Hosoda K, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 1992;130: w35x Rademaker MT, Charles CJ, Kosoglou T, et al. Clearance receptors and endopeptidase: equal role in natriuretic peptide metabolism in heart failure. Am J Physiol 1997;273:H2372 H2379. w36x Kishimoto I, Nakao K, Suga S, et al. Downregulation of C- receptor by natriuretic peptides via ANP-B receptor in vascular smooth muscle cells. Am J Physiol 1993;265:H1373 H1379. w37x Bruneau BG, Piazza LA, de Bold AJ. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria. Am J Physiol 1997;273:H2678 H2686. w38x Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circulation 2000;102: w39x Riddervold F, Smiseth OA, Hall C, Groves G, Risoe C. Rateinduced increase in plasma atrial natriuretic factor can occur independently of changes in atrial wall stretch. Am J Physiol 1991;260:H1953 H1958. w40x Nishimori T, Tsujino M, Sato K, Imai T, Marumo F, Hirata Y. Dexamethasone-induced up-regulation of adrenomedullin and atrial natriuretic peptide genes in cultured rat ventricular myocytes. J Mol Cell Cardiol 1997;29: w41x Qi W, Mathisen P, Kjekshus J, et al. Natriuretic peptides in patients with aortic stenosis. Am Heart J 2001;142: w42x Haug C, Metzele A, Kochs M, Hombach V, Grunert A. Plasma brain natriuretic peptide and atrial natriuretic peptide concentrations correlate with left ventricular end-diastolic pressure. Clin Cardiol 1993;16: w43x Hama N, Itoh H, Shirakami G, et al. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995;92: w44x Sumida H, Yasue H, Yoshimura M, et al. Comparison of secretion pattern between A-type and B-type natriuretic peptides in patients with old myocardial infarction. J Am Coll Cardiol 1995;25: w45x Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation 1994;90: w46x Langenickel T, Pagel I, Hohnel K, Dietz R, Willenbrock R. Differential regulation of cardiac ANP and BNP mrna in different stages of experimental heart failure. Am J Physiol Heart Circ Physiol 2000;278:H1500 H1506. w47x Yoshimura M, Yasue H, Okumura K, et al. Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide

8 268 M. Vanderheyden et al. / The European Journal of Heart Failure 6 (2004) in patients with congestive heart failure. Circulation 1993;87: w48x Weidmann P, Hasler L, Gnadinger MP, et al. Blood levels and renal effects of atrial natriuretic peptide in normal man. J Clin Invest 1986;77: w49x Zeidel ML, Kikeri D, Silva P, Burrowes M, Brenner BM. Atrial natriuretic peptides inhibit conductive sodium uptake by rabbit inner medullary collecting duct cells. J Clin Invest 1988;82: w50x Richards AM, McDonald D, Fitzpatrick MA, et al. Atrial natriuretic hormone has biological effects in man at physiological plasma concentrations. J Clin Endocrinol Metab 1988;67: w51x Kasahara M, Mukoyama M, Sugawara A, et al. Ameliorated glomerular injury in mice overexpressing brain natriuretic peptide with renal ablation. J Am Soc Nephrol 2000;11: w52x Tamura N, Ogawa Y, Chusho H, et al. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci USA 2000;97: w53x Schultz HD, Gardner DG, Deschepper CF, Coleridge HM, Coleridge JC. Vagal C-fiber blockade abolishes sympathetic inhibition by atrial natriuretic factor. Am J Physiol 1988;255:R6 R13.