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Review TRENDS in Endocrinology and Metabolism Vol.16 No.

10 December 2005

The endocrine function of the heart


Monica Forero McGrath, Mercedes L. Kuroski de Bold and Adolfo J. de Bold
Cardiovascular Endocrinology Laboratory, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa,
Ontario, K1Y 4W7, Canada

Atrial cardiocytes in the heart of mammals produce in a (BNP) also referred to as B-type natriuretic peptide [6] and
regulated manner the polypeptide hormones atrial C-type natriuretic peptide (CNP) [7]. ANF and BNP are
natriuretic factor (ANF, ANP) and brain natriuretic primarily synthesized in the heart muscle cells of the atria
peptide (BNP). The biological actions of ANF and BNP (atrial cardiocytes), whereas CNP is synthesized in the
are similar; they include the modulation of systems that vascular endothelium. ANF and BNP are synthesized in
tend to increase extracellular fluid volume and blood comparatively small amounts in the heart ventricles and
pressure, such as the renin–angiotensin system and the in several non-cardiac sites, including the central nervous
sympathetic nervous system. Additionally, both hor- system, gonads and kidneys. ANF and BNP share similar
mones have potent growth-regulating properties. ANF biological activities. The net effect of these activities is
and BNP signal by activating membrane-bound guanylyl the reduction of cardiac preload and afterload and the
cyclase receptors, leading to an increase in intracellular modulation of cardiovascular growth [8,9]. Although ANF
cGMP and thus affecting the activity of cGMP-regulated and BNP are most often associated with the endocrine
enzymes and ion channels. Under chronic hemodynamic function of the heart, it should be noted that other
overload, cardiac ANF and BNP synthesis and secretion hormones are synthesized in the heart as well. These
are increased. This increase is viewed as a cardioprotec- include adrenomedullin (AM), cardiotophin-1 (CT-1) and
tive mechanism, given the beneficial effects of ANF and aldosterone. This article focuses on ANF and BNP and the
BNP on cardiac preload, afterload and cardiovascular emerging areas of cardiac NP research.
growth. As discussed in this review, some basic facts
regarding the synthesis and secretion of ANF and BNP Actions associated with ANF and BNP
and their peripheral effects remain to be clarified. The modulation of cardiovascular function by ANF and
Nevertheless, at the clinical level, the elevation of BNP takes place at a number of different levels (Figure 1).
circulating ANF and BNP in heart failure or following These hormones directly affect blood vessel function by
acute coronary syndromes has been shown to have decreasing vascular smooth muscle tone and thus
diagnostic and prognostic implications. Moreover, these peripheral vascular resistance, and by increasing capil-
peptides themselves hold promise as therapeutic agents lary permeability [10]. This generates a significant
in the treatment of heart failure. Additional pharmaceu- increase in hematocrit [3].
tical applications might be gleaned from current ANF and BNP have multiple actions on
preclinical and clinical studies showing beneficial effects nerve activity. ANF reduces cardiac and pulmonary
of ANF or BNP in the treatment of hypertension, chemo- and baroreceptor activity, which leads to the
bronchospasm and in tissue remodeling following suppression of sympathetic outflow to the heart. A
acute myocardial infarction. diminished sympathetic activity together with an increase
in vagal afferent activity leads to a reduction in heart rate
Historical context and cardiac output [10]. Salt and water appetite is
Early electron microscopic studies of the atria of the negatively influenced by ANF and BNP, thus leading to
heart in mammals suggested on a phenotypic basis a a reduction in extracellular fluid volume [11]. Also, ANF
mixed secretory and contractile function for atrial suppresses water reabsorption by inhibiting vasopressin
cardiocytes [1,2]. However, the endocrine function of secretion from the posterior pituitary. This inhibitory
the heart was first established unequivocally by inves- action is sustained even in acute hemorrhage or prolonged
tigations in which injections of atrial, but not ventri- dehydration [12]. Furthermore, blunting of renal sym-
cular, extracts into bioassay rats were found to produce pathetic nerve activity by ANF and BNP results in a
a strong natriuresis and diuresis as well as hypotension reduction in NaC reabsorption.
accompanied by an increase in hematocrit [3]. This The powerful natriuretic and diuretic effects of ANF
factor, named atrial natriuretic factor (ANF) or, later, and BNP are mainly related to an increase in glomerular
atrial natriuretic peptide (ANP), was first isolated, filtration rate and filtration fraction as well as the
purified and sequenced from rat atrial extracts [4]. inhibition of NaC reabsorption at the level of the collecting
This work was followed by the isolation of related duct [13,14]. The increase in glomerular filtration rate and
members of a family of natriuretic peptides (NP), filtration fraction results from dilatation of afferent
including human ANF [5], brain natriuretic peptide arterioles and constriction of efferent arterioles, which
Corresponding author: de Bold, A.J. (adebold@ottawaheart.ca). leads to an increase in glomerular capillary hydraulic
Available online 2 November 2005 pressure. These actions enhance the driving force for
www.sciencedirect.com 1043-2760/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tem.2005.10.007
470 Review TRENDS in Endocrinology and Metabolism Vol.16 No.10 December 2005

Endocrine heart

ANF and BNP

NPR-A

cGMP ↑

Kidney:
Vessels:
• Glomerular effects:
Tone ↓
Blood
Afferent arteriole tone ↓ ↓ pressure
Capillary
permeability ↑
Efferent arteriole tone ↑

Glomerular filtration ↑ Cell proliferation:


Blood flow ↑ Smooth muscle cells ↓
Diuresis
and and myofibroblasts
Renin release ↓
natriuresis
• Tubular effects: Nervous system:
Na+
Collecting duct Renal sympathetic ↓ reabsorption
sodium reabsorption ↓ activity ↓
Renin

release
Starling forces ↓ Cardiac and pulmonary
Compensatory
chemio-and baro- ↓ ↓
Osmotic gradient ↓ receptors
reflexes

Adrenal cortex:

Aldosterone ↓ Na+ Salt and water ↓ ↓ Extracellular


synthesis and release ↓ reabsorption appetite fluid volume

Release of ↓ ↓ H2O
antidiuretic hormone reabsorption

TRENDS in Endocrinology & Metabolism

Figure 1. The biological actions of ANF and BNP are mediated by the natriuretic peptide receptor type A (NPR-A). Interaction of the natriuretic peptide ligand with the receptor
leads to an increase in intracellular cyclic guanosine monophosphate (cGMP), which mediates the effects shown in different tissues by interaction with cGMP-dependent
protein kinases, diesterases andcGMP-gated ion channels.

ultrafiltration and also contribute to an unfavorable BNP appears to inhibit cardiac intersitium remodeling
gradient for NaC and water reabsorption [15]. through its antifibrotic effects [22]. BNP inhibition of
Both ANF and BNP have potent inhibitory effects on transforming growth factor-b-induced fibrosis was
the renin–angiotensin–aldosterone system. In heart fail- recently shown to be associated with cGMP-dependent
ure, activation of the renin–angiotensin–aldosterone protein kinase and MEK/ERK pathways [23].
system is suppressed by ANF and BNP through direct
inhibition of aldosterone synthesis and secretion [16] and Importance of the function of the endocrine heart
by suppression of renin release [17,18]. The importance of the function of the endocrine heart is
ANF and BNP possess growth-suppressing and anti- reflected by the fact that genetic disruption of the ANF or
proliferative properties. ANF has been shown to inhibit BNP genes or blockade of its receptor results in
vascular smooth muscle cell proliferation in culture and impairment of cardiorenal homeostasis [24–26]. ANF
angiotensin-induced hypertrophy [19,20]. Growth-pro- receptor type A (NPR-A) blockade or genetic disruption
moting effects generated by norepinephrine were also leads to salt-sensitive or salt-insensitive hypertension,
shown to be inhibited by ANF treatment on both respectively, in homozygous null mice [27,28]. In NPR-A-
cardiocytes and fibroblasts [21]. Other cell types, such as deficient homozygous mice, volume expansion fails to
cultured endothelial cells, respond similarly to NP induce diuresis and natriuresis or to increase cGMP
treatment [10]. excretion as observed in wild-type mice treated identically
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Review TRENDS in Endocrinology and Metabolism Vol.16 No.10 December 2005 471

ANF 99 126
Ser-Leu-Arg-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Met-Asp-Arg-Ile-Gly-Ala-Gln-Ser-Gly-Leu-Gly-Cys-Asn-Ser-Phe- Arg-Tyr

BNP
77 108
Ser-Pro-Lys-Met-Val-Gln-Gly-Ser-Gly-Cys-Phe-Gly-Arg-Lys-Met-Asp-Arg-Ile-Ser-Ser-Ser-Ser-Gly-Leu-Gly-Cys-Lys-Val-Leu-Arg-Arg-His

82 103
CNP
Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys

TRENDS in Endocrinology & Metabolism

Figure 2. Primary structure of human ANF, BNP and CNP. These polypeptide hormones share a 17-amino acid ring formed by a disulfide linkage between two cysteine
residues.

[28]. In another NPR-A knockout model, absence N-terminal-proBNP1–76 [37,38]. In atrial cardiocytes, ANF
of NPR-A causes hypertension and leads to cardiac and BNP are stored together in storage organelles
hypertrophy with extensive interstitial fibrosis and, referred to as specific atrial granules. The C-terminal
particularly in males, to sudden death [29]. BNP knock- portions of all NP share a 17-amino acid ring formed by a
outs do not develop hypertension or cardiac hypertrophy disulfide linkage between two cysteines. This ring
but show cardiac fibrosis [30]. structure is essential for biological activity [39] (Figure 2).
The final processing step involved in the maturation of
Biochemistry of ANF and BNP ANF appears to be undertaken by serine proteases. Corin,
Two distinct genes, Nppa and Nppb, encode ANF and a type II transmembrane serine protease, can convert
BNP, respectively. In humans, both genes are located on ANF1–126 to ANF99–126. Corin has also been linked to
the distal short arm of chromosome 1 (1p36.2), whereas in proBNP processing [40].
the mouse and in the rat, these genes reside on
chromosomes 4 and 5, respectively. The sequences
encoding these peptides are located on the same DNA Cardiac expression and secretion of ANF and BNP
strand and are organized in tandem [31]. In humans, The greater part of ANF and BNP gene expression is
Nppb is located w8 kb from Nppa [32]. found in the atria of the heart (1–3% of total mRNA).
The structures of the ANF- and BNP-encoding genes Other sites, such as the ventricles and aortic arch, as well
are similar, and are composed of three exons separated by as extra-cardiac tissues, also express ANF and BNP, albeit
two introns. The signal sequence is located in exon 1, at much lower levels than the atria [41,42]. Cultured
whereas the majority of the protein-coding sequences, cardiac fibroblasts produce BNP [43]. ANF mRNA
which also contain the bioactive portion of the molecule, expression has been shown in fibroblasts located in
are found in exon 2. In the rat, exon 3 encodes a Tyr-Arg- infracted tissue, which corresponds with the transition
Arg sequence. The Arg-Arg pair is removed by post- of these cells to myofibroblasts [44]. The relative contri-
translational events [33]. In humans, these two bution and importance of NP production by fibroblasts in
C-terminal arginine residues are absent [34]. either endocrine, paracrine or autocrine terms remains to
ANF has a high degree of homology across mammals be determined. ANF, BNP and CNP, as well as NPR-A and
[31]. A single nucleotide codon substitution results in a NPR-B transcript and protein, are highly expressed by
change of an isoleucine residue in position 110 for rats, myofibroblasts in human coronary atheromas [45].
mice and rabbits into a methionine residue for humans, Basal circulating levels of ANF and BNP arise from
dogs and cows [10]. In contrast to ANF, BNP is continual secretion of ANF and BNP from the atria. In
comparatively poorly conserved. Mature BNP from humans, ANF and BNP plasma levels are significantly
sheep, cow, pig and dog share sequence homologies [35]. correlated with age and gender [46]. In subjects without
known cardiovascular, renal or pulmonary disease, BNP
Biosynthesis of ANF and BNP levels are higher in women than in men, and these levels
In humans, ANF and BNP are synthesized as 151- and increase with age within each gender [47].
134-amino acid preprohormones, respectively. The Increased secretion of both ANF and BNP is observed
removal of the N-terminal signal peptide generates under conditions of increased hemodynamic load.
proANF (ANF1–126) and proBNP (BNP1–108) [36]. ANF is Development of cardiac hypertrophy is accompanied by a
stored as the precursor form proANF1–126 and is further re-expression of fetal genes, which entail increased
processed during secretion at the monobasic cleavage site production and secretion of ANF and BNP by the
Arg98-Ser99 into the circulating biologically active form ventricles [48]. However, the amount secreted from the
ANF99–126 and the N-terminal-ANF1–98 form. BNP, how- ventricles remains lower than that from the atria. In
ever, is stored as a C-terminal bioactive BNP77–108 and an isolated perfused hearts from spontaneously hypertensive
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472 Review TRENDS in Endocrinology and Metabolism Vol.16 No.10 December 2005

rats, only 38% of BNP and 16% of ANF originate from the Prior to and during cardiac allograph rejection episodes,
ventricles [42]. BNP secretion is selectively unregulated [61]. In neonatal
In deoxycorticosterone acetate-salt-induced left ventri- rat ventricular cardiocytes, the proinflammatory cyto-
cular hypertrophy in the rat, BNP content was higher in kines tumor necrosis factor-a (TNF-a) and interleukin
the atria than in the ventricles, even taking into account (IL)-1b (IL-1b) significantly increase BNP gene expression
the differences in mass between the atrial and ventricular and secretion, whereas ANF gene expression and
chambers [38]. Catheterization studies in patients with secretion are not altered [62]. As yet, unidentified
left ventricular hypertrophy demonstrated that BNP proinflammatory cytokines might also be involved.
plasma concentration between the anterior interventri- Conditioned medium from alloactivated T lymphocyte
cular vein and the coronary sinus was significantly higher cultures, which do not contain detectable amounts of
than in the control group. This finding points out a TNF-a or IL-1b have the same effect as these cytokines on
significant contribution to increased BNP circulating BNP expression. The p38 MAP kinase inhibitor SB203580
levels of the atria in cardiac hypertrophy [49]. blunts the cytokine-stimulated upregulation of BNP gene
The endocrine heart responds differently to hemody- expression and secretion, as well as increased BNP
namic increases in load, depending on whether the promoter activity [62].
challenge is acute, subacute or chronic (reviewed in
[50]). Enhanced secretion of ANF and BNP from the NP receptors
atria is observed following acute mechanical muscle The biological effects of ANF and BNP are predominantly
stretch. This phenomenon is referred to as ‘stretch– mediated through the NPR-A, a guanylyl cyclase-coupled
secretion coupling’ [51]. This type of secretion relies on a receptor widely distributed throughout the body, includ-
depletable pool of NP and is independent of NP ing the kidneys, vascular smooth muscle, adrenal glands,
synthesis [52]. brain and heart. A second guanylyl cyclase-coupled
Recent in vitro studies showed that pertussis toxin can receptor (NPR-B) is associated with CNP signaling.
completely abolish stretch-induced ANF secretion, thus Three domains are recognized in the NPRs: an extracellu-
indicating the involvement of G i/o proteins in this lar ligand-binding domain that binds to NP, a short
phenomenon. Immunohistochemical analysis of the atria transmembrane domain and an intracellular domain
demonstrated partial co-localization of Gao subunit and that acts as a docking site for other proteins [63]. The
ANF. Strong Gao staining was also observed along the extracellular ligand-binding domain has poor sequence
sarcolemma [53]. Microarray analysis (Forero et al., homology among the NPRs. This low sequence similarity
unpublished) reveals significant differential expression might impact on the NP affinities to different NPRs.
of the Gao isoform 1 on atrial over ventricular muscle. Agonist binding to NP receptors results in an increase
Subacute hemodynamic overload, as seen during in intracellular cGMP, thus elevating urinary and
mineralocorticoid escape, is characterized by a unique circulating levels of cGMP after the systemic adminis-
increase in atrial ANF and BNP synthesis, in which tration of ANF [64].
plasma ANF, but not BNP, is significantly elevated [26]. Intracellular cGMP targets include cGMP-dependent
Chronic hemodynamic overload results in increased protein kinases (PKGs), cGMP-gated ion channels and
synthesis and secretion of ANF and BNP in both atria and cGMP-regulated cyclic nucleotide phosphodiesterases
ventricles. Conditions such as long-standing arterial [65]. The vasorelaxant effect of NP on vascular smooth
hypertension and chronic congestive heart failure (CHF) muscle cells is, in part, mediated by PKGs. PKG
are accompanied by the ventricular re-expression of the phosphorylates calcium-activated potassium channels
cardiac fetal gene program, which is associated with the and inositol trisphosphate receptor-associated cGMP
re-expression of both ANF and BNP [54,55]. kinase substrates, causing a reduction in cytosolic calcium
In addition to mechanical stimuli, neuroendocrine concentration. This decrease in calcium desensitizes the
agents can act on cardiocytes to modulate ANF and BNP contractile machinery to calcium and leads to muscle
synthesis and secretion. These include endothelin-1 (ET-1) relaxation [66]. cGMP-gated cation channels are inhibited
[56], hydroxyvitamin D3 [57], glucocorticoids, thyroid by ANF [67]. These channels mediate electrogenic NaC
hormone, growth factors, thrombin, angiotensin II (Ang absorption in the inner medullary collecting ducts, thus
II), prostaglandins and a1-adrenergic agonists (reviewed accounting for part of the natriuretic activity of ANF and
in [51]). Some of these substances actively contribute to BNP. Finally, cGMP-regulated phosphodiesterases have
the modulation of ANF and BNP synthesis and secretion various roles in cellular signaling, resulting in the
in both the normal and pathophysiological states [58,59]. regulation of cardiac function, adrenal steroidogenesis
and phototransduction (reviewed in [68]).
Differential regulation of NP gene expression NPR-C is considered to be a clearance receptor,
Although, in general, ANF and BNP respond at the although G-protein signaling has also been associated
transcriptional, translational and secretory levels to a with it [69]. The 37-amino acid cytoplasmic segment of
variety of agonists in a similar manner, there are some NPR-C is characteristic of several receptors involved in
instances in which an uncoordinated regulation of these peptide and macromolecule clearance. NPR-C is found
peptides is observed. In acute myocardial infarction most abundantly in areas receiving large proportions of
(AMI), a rapid ventricular induction of BNP gene the total cardiac output, such as the glomerular and
expression is observed in the early phases, whereas only vascular structures of the kidney and also in the adrenals,
minor changes in ANF gene expression are detected [60]. lungs, brain, in all four cardiac chambers and in
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Review TRENDS in Endocrinology and Metabolism Vol.16 No.10 December 2005 473

the vascular wall. NPR-C can account for 95% of NPRs in mRNA and secretion in cardiocyte cultures [62]. In a
the kidney cortex [70]. recent immunocytochemical study [85], cardiocytes and
During the development of cardiac hypertrophy, a cardiac fibroblasts were reported to display low reactivity
reduction in cardiac NPR-C synthesis is observed, for AM. However, sparsely distributed, strongly AM-
together with an upregulation in ANF and NPR-A gene positive cells reminiscent of mast cells were found near
expression [71]. The structural requirement for ANF the coronary vessels in both atria and ventricles. These
recognition by NPR-C is a linear sequence of eight amino cells also appeared to contain ANF and BNP.
acids, which is much less stringent than the 17-amino acid
ring necessary for ANF binding to NPR-A. NPR-C Cardiotrophin-1
internalization occurs at a rate of 5–7% per minute, Cardiotrophin-1 (CT-1) is an IL-6-related cytokine
which is much faster than NP dissociation, thus ensuring secreted from the heart and is involved in hypertrophic
efficient ligand transport and degradation. Upon intern- and protective actions on cardiocytes [86]. Recent studies
alization, ANF and BNP are hydrolyzed within lysosomes, have demonstrated that CT-1 plasma levels correlate with
whereas NPR-C is recycled to the cell surface [72]. systolic blood pressure [87] and also with left ventricular
The binding potency of the NPRs is ranked as follows: hypertrophy [88] in hypertensive patients. CT-1 plasma
NPR-AZANFRBNP[CNP; NPR-BZCNP[ANFR levels are also elevated in heart failure patients [89]
BNP; NPR-CZANFOCNPRBNP [73]. and following acute myocardial infarction (AMI) [90].
The increase in CT-1 correlates with the severity of left
Metabolic clearance of ANF and BNP ventricular dysfunction.
In addition to NPR-C, NPs are cleared from the circulation
via proteolytic cleavage by neutral endopeptidase (NEP)
24.11 [74]. NEP 24.11 is expressed mainly in the proximal Mineralocorticoids
renal tubules of the kidney, as well as throughout the The concept that the heart produces aldosterone or a
vascular endothelium, lungs and heart. Under pathophy- closely related substance dates back several decades with
siological conditions, when NPR-C is thought to be reports of mineralocorticoid-like activity in isolated heart
saturated, NEP 24.11 contributes significantly to the perfusates [91]. More recently, the role of the heart as a
removal of the NPs [75]. ANF possesses a half life of significant source of aldosterone production has been
about three to five minutes, depending on the species. By questioned, although not completely dismissed [92,93].
contrast, BNP has a half life of 22.6 minutes [73]. This CYP11B2, the enzyme catalyzing the terminal step in
difference is explained by the reduced binding affinity of aldosterone synthesis, is upregulated in the failing human
BNP to NPR-C, which can be by as much as one order of heart [94].
magnitude compared with ANF [76], as well as its slower
rate of hydrolysis by NEP 24.11 (i.e. CNPRANFOBNP). New and emerging pharmaceutical applications of NP
Most studies using ANF in humans have been carried out
Other cardiac hormones in a hospital setting using intravenous (iv) administration
In a classical sense, the endocrine heart is represented by of synthetic ANF. An iv injection of ANF to patients with
atrial cardiocytes because they display organelles associ- hypertension or CHF results in a decrease in systolic blood
ated with the vectorial transport, package and storage of pressure, preload, afterload, renin activity and an
polypeptide hormones. There are other hormones, how- improvement in left ventricular performance [95–99].
ever, that are secreted from the heart, albeit Long-term iv administration of ANF (Carperitidew) for
not exclusively. seven days in patients with acute CHF ‘who resisted
various therapies’, showed a significant hemodynamic
Cardiac adrenomedullin improvement 48 h after the start of the infusion. These
Adrenomedullin (AM) is a highly conserved, 52-amino acid patients showed a significant decrease in mean pulmonary
peptide that contains a six-residue ring structure formed wedge pressure, mean right atrial pressure and systemic
by a disulfide linkage [77]. In common with the NPs, AM vascular resistance but no changes in systolic blood
has hypotensive, diuretic and natriuretic properties [78] pressure or heart rate [100]. Hayashi et al. [101] showed
but its role in the development of cardiac pathologies is that a 24 h infusion of ANF (0.025 mg/kg/min) in patients
less clear. Plasma AM concentration is increased in with first anterior AMI prevented left ventricular remo-
patients with cardiovascular diseases such as systemic deling and improved left ventricular ejection fraction. In
arterial hypertension and congestive heart failure, and in addition, plasma levels of aldosterone, ET-1 and Ang II
patients with renal failure and septic shock [79]. The were significantly decreased during the ANF infusion. It
source of increased AM in cardiac failure is the heart [80], was suggested that the beneficial effects of ANF admin-
and the plasma levels of AM correlate with the severity of istration in these patients might be partly due to the
failure. Given that cardiocytes possess AM receptors [81] suppression of aldosterone, ET-1 and Ang II secretion.
and that AM inhibits protein synthesis in cardiocyte The efficacy and safety assessment for Carperitidew
cultures [82], it is to be expected that AM can act as an was assessed in a six-year prospective study of 3777
antihypertrophic agent. Investigations using cell cultures patients with acute heart failure; w51% of the patients
have shown that the pro-inflammatory cytokines TNF-a were assessed as class III or IV according to the Killip
and IL-1b stimulate AM secretion from non-cardiocytes classification [102]. The patients were treated with
[83,84]. The same cytokines specifically upregulate BNP Carperitidew at 0.085 mg/kg/min for 65 h. Significant
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474 Review TRENDS in Endocrinology and Metabolism Vol.16 No.10 December 2005

hemodynamic improvement was observed in 82% of isolated hearts obtained from rats chronically treated with
the patients. omapatrilat [112].
The ‘Japan-Working Groups of Acute Myocardial Chronic oral NEP inhibition by candoxatril in a CHF
Infarction for the Reduction of Necrotic Damage by ANP’ animal model has been recently shown to increase sodium
is carrying out a prospective, randomized, multicenter excretion, enhance ANF plasma levels and suppress
study to evaluate the effects of ANF as an adjunct therapy aldosterone activation, thus suggesting a therapeutic
for AMI and post-MI [103]. application with particular reference to delaying the
Beneficial effects of iv ANF administration after AMI reduction in sodium excretion observed in the transition
were recently reported by Kuga et al. [104] in a small from early to severe CHF [113].
group of patients. The patients received an intracoronary Clinical applications of NP under development include
bolus of ANF (25 mg) during angioplasty within 12 h after the use of BNP as a bronchodilator for asthmatic patients
AMI, and an iv infusion of 0.0025 mg/kg/min was initiated [114] as well as in the treatment of immune-mediated
on admission and maintained for one week. A similar renal injury [115].
group of patients received saline. ANF-treated patients
showed a significant increase in left ventricular ejection Conclusions and perspectives
fraction. Left ventricular end-diastolic volume index The discovery of the endocrine function of the heart has
decreased significantly at six months, compared with led to numerous new insights in both basic knowledge and
saline-treated patients. Left ventricular regional wall in clinically oriented areas. The overall concept emerging
motion of the infarcted segments also increased signifi- is that ANF and BNP are produced by the heart to
cantly in the ANF group. These results suggest that modulate its own workload in health and disease through
administration of ANF prevented reperfusion injury to the a variety of mechanisms. In this respect, less clear is the
myocardium and conserved left ventricular function by role of other cardiac hormones either as circulating or
improving regional wall motion of the infarcted segments. locally acting hormones.
Finally, chronic infusion (O48 h) of ANF (50 mg/kg/min) There are several areas that remain to be clarified in
was shown to improve renal blood flow and glomerular order to better understand the processes regulating NP
filtration rate in patients with acute renal impairment gene expression and secretion. As discussed above,
associated with cardiac surgery [105]. stretch-coupled secretion can now be associated with a
Natrecorw (nesiritide), a recombinant form of human Gi/o protein. However, the receptor associated with this
BNP, has been approved for the iv treatment of patients protein remains to be characterized as does the influence
with acutely decompensated CHF who have dyspnea at on NP production of the neuroendocrine activation
rest or with minimal activity [106]. Subcutaneous observed in heart failure, a process which, similarly
administration of nesiritide induces beneficial cardiorenal to mechanical stimulation, is known to increase NP
and neurohumoral actions [107]. A meta-analysis of production. These basic processes are important to under-
randomized, controlled trials using nesiritide claimed an stand because, given the favorable response obtained in
increased risk of death within the first month after essential hypertension and chronic congestive heart
nesiritide treatment compared with control therapies in failure to exogenously administered NP, both these
acute decompensated CHF patients (35 of 485 versus 15 of entities may be described as states of relative
377, respectively) [108]. A recently published study NP deficiency.
designed to compare the in-hospital mortality of patients The uncoordinated expression of ANF and BNP
with acute decompensated heart failure treated with induced by some pro-inflammatory cytokines is puzzling,
nesiritide with those treated with nitroglycerin concluded and its mechanism and significance remain to be
that risk of in-hospital mortality was similar for these two determined. An understanding of selective BNP upregula-
agents [109]. New and adequately powered trials are tion might hold the key to explaining its coexistence with
needed to settle this issue. ANF, a hormone with which it shares biological properties
As an alternative to NP infusions, orally active and receptor type. On the more practical side, investi-
inhibitors of NEP 24.11, referred to as vasopeptidase gations in this field might help to rationalize the use of one
inhibitors, have been clinically evaluated. These com- hormone over the other for diagnostic, prognostic or
pounds prevent the catabolic clearance of natriuretic therapeutic purposes. In the latter regard, the above-
peptides, potentiate the effects of bradykinin and are discussed properties of NP in the regulation of cell tone,
also angiotensin-converting enzyme inhibitors. A promi- growth and in cardiac remodeling appear particularly
nent example is omapatrilat, a very effective antihyper- interesting to pursue clinically.
tensive agent (reviewed in [110]). The clinical use of Indeed, the measurement of plasma NP levels is now an
omapatrilat in the treatment of hypertension, however, important tool in the diagnosis of CHF and acute coronary
has been seriously hindered by the risk of angioedema, syndromes [116]. Finally, the therapeutic application of
which was found to be greater with this drug than with the ANF and BNP has developed into an active area of inquiry
angiotensin-converting enzyme inhibitor enalapril and [117] either by the use of the hormones themselves or by
was further increased in African-Americans and in preventing their degradation and hence increasing the
patients who smoked [111]. effective circulating levels of the hormones [118]. A long-
Recently, it was found that omapatrilat improved the acting form of ANF or BNP, if developed, has the potential
functional recovery of the heart and reduced left ventricular to replace the polypharmacy used in the treatment of
end-diastolic pressure following ischemia–reperfusion in chronic CHF and essential hypertension. Furthermore,
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Review TRENDS in Endocrinology and Metabolism Vol.16 No.10 December 2005 475

the elevated expression of NP and their receptors in 22 Tamura, N. et al. (2000) Cardiac fibrosis in mice lacking brain
human coronary atheromas suggests that a line natriuretic peptide. Proc. Natl. Acad. Sci. U. S. A. 97, 4239–4244
23 Kapoun, A.M. et al. (2004) B-type natriuretic peptide exerts broad
of research following this observation might provide functional opposition to transforming growth factor-beta in primary
important information on the natural history of the human cardiac fibroblasts: fibrosis, myofibroblast conversion, pro-
disease and potential therapeutic application of NP in liferation, and inflammation. Circ. Res. 94, 453–461
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