International review of cell and molecular biology

International Review of Cell and Molecular Biology V O L U M E T W O E I G H T Y INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY Series Editors GEOFFREY H BOURNE 1949–1988 JAMES F DANIELLI 1949–1984 KWANG W JEON 1967– MARTIN FRIEDLANDER 1984–1992 JONATHAN JARVIK 1993–1995 Editorial Advisory Board ISAIAH ARKIN KEITH LATHAM PETER L BEECH WALLACE F MARSHALL ROBERT A BLOODGOOD BRUCE D MCKEE DEAN BOK MICHAEL MELKONIAN KEITH BURRIDGE KEITH E MOSTOV.

V O L U M E T W O E I G H T Y

CELL AND MOLECULAR BIOLOGY

Editorial Advisory Board

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1 Natriuretic Peptides in the Regulation of the

Andrea Porzionato, Veronica Macchi, Marcin Rucinski,

Ludwik K Malendowicz, and Raffaele De Caro

2 Biology of Natriuretic Peptides and Their Receptors 2

3 Expression of Natriuretic Peptides and Their Receptors

4 Effects of Natriuretic Peptides on the HPA Axis 12

5 Natriuretic Peptides and Pathophysiology of HPA Axis 21

2 Evidence for Multiple Photosystems in Jellyfish 41

Anders Garm and Peter Ekstro ¨m

6 Multiple Opsins in Cnidarians—Multiple Photosystems? 70

3 Membrane Trafficking in Protozoa: SNARE Proteins,

H+-ATPase, Actin, and Other Key Players in Ciliates 79

4 Exocytosis and Endocytosis 124

5 Possible SNARE Arrangement in Microdomains

7 Calcium-Binding Proteins and Calcium Sensors 142

8 Additional Aspects of Vesicle Trafficking 146

9 Emerging Aspects of Vesicle Trafficking in Ciliates 152

5 Impact of ATP-Binding Cassette Transporters

Johanna Weiss and Walter Emil Haefeli

2 Drug Therapy of HIV-1: Drug Classes and Site of Action 221

3 ABC-Transporters Influencing Drug Therapy

4 Cell Models Investigating the Impact of ABC-Transporters

5 Anti-HIV-1 Drugs as Substrates, Inhibitors, and Inducers

of ABC-Transporters: In Vitro and In Vivo Findings 236

6 Clinically Relevant Drug Interactions with Anti-HIV-1 Drugs

7 ABC-Transporters, ‘‘Cellular’’ Resistance,

8 ABC-Transporter Polymorphisms and HIV-1 262

6 New Insights into the Circadian Clock

4 Input Pathways to the Circadian Oscillator

Walter Emil Haefeli

Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany

Natriuretic Peptides in the

Regulation of the Hypothalamic–

Pituitary–Adrenal Axis

Andrea Porzionato,* Veronica Macchi,* Marcin Rucinski,†

Ludwik K Malendowicz,†and Raffaele De Caro*

Contents

2 Biology of Natriuretic Peptides and Their Receptors 2

2.2 Natriuretic peptide receptors and their signaling mechanisms 4

3 Expression of Natriuretic Peptides and Their Receptors in the

International Review of Cell and Molecular Biology, Volume 280 # 2010 Elsevier Inc ISSN 1937-6448, DOI: 10.1016/S1937-6448(10)80001-2 All rights reserved.

* Department of Human Anatomy and Physiology, University of Padova, Padova, Italy

{ Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland

1

peptides from the circulation but it also acts through inhibition of adenylyl cyclase NPR-A binds ANP and BNP; NPR-B preferentially binds CNP; and NPR-C binds all natriuretic peptides with similar affinities All natriuretic peptides and their recep- tors are widely present in the hypothalamus, pituitary, adrenal cortex, and medulla.

In the hypothalamus, they reduce norepinephrine release, inhibit oxytocin, pressin, corticotropin-releasing factor, and luteinizing hormone-releasing hormone release In the hypophysis, natriuretic peptides inhibit basal and induced ACTH release Conversely, the effects of natriuretic peptides on secretion of growth, luteinizing, and follicle-stimulating hormones are not clear Natriuretic peptides are known to inhibit basal and stimulated aldosterone secretion, through an increase

vaso-of intracellular cGMP, and to inhibit the growth vaso-of zona glomerulosa Inhibition or stimulation of glucocorticoid secretion by adrenocortical cells has been reported

on the basis of the species involved, and an indirect effect mediated by medullary cells has been hypothesized In the adrenal medulla, natriuretic pep- tides inhibit catecholamine release and increase catecholamine uptake It appears that natriuretic peptides may play a role in the pathophysiology of adrenocortical neoplasias and pheochromocytomas.

adrenal-Key Words: Natriuretic peptides, Hypothalamic–pituitary–adrenal axis, ACTH secretion, Catecholamine secretion, Pheochromocytomas ß 2010 Elsevier Inc.

1 Introduction

Numerous neuropeptides control the hypothalamic–pituitary–adrenal(HPA) axis, acting on both its central and peripheral branch Natriureticpeptides are known to be included in this group of regulatory peptides, butonly a few review articles have been published regarding the role of natriureticpeptides in the HPA axis, and mainly with reference to specific structures orspecific pathological conditions (Gutkowska et al., 1997; Wiedemann et al.,2000) A comprehensive and updated review on the role of natriuretic peptides

in all the levels of the HPA axis is still lacking Thus, after a synthetic account onthe biology of the natriuretic peptides system, we will herein review dataindicating how natriuretic peptides and their receptors are expressed in allthe anatomical components of the HPA axis, and are involved in the functionalregulation of HPA axis under both physiological and pathological conditions

2 Biology of Natriuretic Peptides and Their Receptors

2.1 Natriuretic peptides

Natriuretic peptides represent a family of three hormones called atrial uretic peptides (ANP) (Kangawa and Matsuo, 1984), brain natriuretic peptides(BNP) (Sudoh et al., 1988), and C-type natriuretic peptides (CNP) (Sudoh

natri-et al., 1990) ANP is a 28-amino acid peptide which has first been isolated fromhuman atrial extract (Kangawa and Matsuo, 1984) BNP and CNP have beenidentified in the porcine brain (Sudoh et al., 1988, 1990) Figure 1.1 shows thesequences of natriuretic peptides All peptides contain the conserved sequenceFGXXXDRIGXXSGL The flanking cysteines form a 17-amino acid disul-fide-linked ring that is required for biological activity In some tissues, CNP-53

is cleaved to CNP-22

26

ANP 1

BNP-32

g-BNP (pro-BNP, in blood)

2.2 Natriuretic peptide receptors and their signaling

mechanisms

The biological activity of the natriuretic peptides occurs via the activation ofthree different receptors, which have been cloned and pharmacologicallycharacterized: NPR-A, NPR-B, and NPR-C The first two receptors arecoupled with guanylate cyclase They consist of an extracellular ligand-bindingdomain, a short transmembrane region, a juxtamembranous protein kinase-homology domain, an alpha-helical or hinge region, and a C-terminal guanylylcyclase catalytic domain, receptor dimerization being essential for the activation

of the catalytic domain (reviewed in Anand-Srivastava and Trachte, 1993;Kuhn, 2003; Maack, 1992; Potter et al., 2006, 2009) Alternative splicing ofNPR-A has recently been found to produce an isoform which does not bindANP and may inhibit ligand-inducible cGMP generation by forming hetero-dimers with the wild-type receptor (Hartmann et al., 2008) NPR-A is acti-vated by ANP and BNP, ANP being more effective than BNP in stimulatingcGMP production NPR-B binds with higher affinity CNP (Fig 1.2) Allnatriuretic peptide receptors are also known to be internalized and to someextent recycled as a result of ligand binding (reviewed in Pandey, 2009).NPR-C binds all three natriuretic peptides with relatively similar affi-nities (Maack, 1992) It is a disulfide-linked homodimer with a singletransmembrane domain which lacks the intracellular guanylate cyclasedomain but is able to internalize natriuretic peptides after binding Thus,

it has first been considered to be involved in removing natriuretic peptidesfrom the circulation (Fig 1.2) Nevertheless, following studies suggestedthat NPR-C contains a 37-amino acid intracellular domain which is able toinhibit the adenylyl cyclase and activate phospholipase C, through activa-tion of Gi proteins Moreover, NPR-C may also inhibit the mitogen-activated protein kinase pathway (signaling pathways of NPR-C reviewed

BNP-32 CNP-22 ANP-28

GC cGMP

cGMP KHD

KHD

cGMP GTP

Figure 1.2 Interaction of ANP, BNP, and CNP natriuretic peptides with receptors NPA-R, NPB-R, and NPC-R NPR-A and NPR-B are membrane-bound guanylyl cyclases, NPR-C—not coupled to guanylyl cyclase—is involved in clearance and metabolism of natriuretic peptides KHD, kinase homology domain.

neurons of several mammal hypothalamic and nonhypothalamic brain tures, such as the septum, anteroventral region of the third ventricle (AV3V),subfornical organum, paraventricular nucleus (PVN), preoptic, supraoptic(SON), infundibular and ventromedial nuclei, lateral hypothalamus, organumvasculosum lamina terminalis, median eminence, lamina terminalis, periaque-ductal gray matter, parabrachial nucleus, solitary tract nucleus, tegmental lateraldorsal nucleus, and periventricular regions (e.g., Chriguer et al., 2001;Gutkowska et al., 1997; Jirikowski et al., 1986; Kawata et al., 1985; Raidoo

struc-et al., 1998; Standaert struc-et al., 1986a; Tanaka struc-et al., 1984) Most reactive neurons in the PVN belong to the parvocellular division ( Jirikowski

ANP-immuno-et al., 1986; Kawata ANP-immuno-et al., 1985), but colocalization of ANP and oxytocin (OT)immunostaining has also been reported in some magnocellular neurons of themagnocellular division of the PVN and SON (Chriguer et al., 2001;Gutkowska et al., 1997; Jirikowski et al., 1986; Kawata et al., 1985) Thedensest terminal fields of ANP-containing fibers have been reported in thePVN of the hypothalamus, the bed nucleus of the stria terminalis, the inter-peduncular nucleus, and the median eminence (Standaert et al., 1986a), whereANP may modulate the release of anterior pituitary hormones (Franci et al.,

1990, 1992; Gutkowska et al., 1997) It has also been reported that containing neurons in the PVN are the major source of ANP-containing nerveterminals in the median eminence (Palkovits et al., 1987) ANP-immunoreac-tive fibers have also been observed in close proximity with oxytocinergic fibers

ANP-in the median emANP-inence (Chriguer et al., 2001) In the hypophyseal portalblood, ANP has been found in 3–4 times higher concentrations than in theperipheral blood and the predominant species of IR-ANP in extracts of portalblood from adult rats is ANP(5–28), whereas in peripheral blood is ANP(1–28)(Lim et al., 1994) ANP mRNA has also been identified in the rat hypothala-mus (Chen et al., 1992; Dagnino et al., 1991; Gardner et al., 1987; Komatsu

et al., 1992) The distribution of mRNA encoding prepro-ANP has also beeninvestigated in rat brain by in situ hybridization and the highest relative con-centrations have been detected in the anteromedial preoptic nucleus of themedial preoptic area (Gundlach and Knobe, 1992; Ryan et al., 1997).Analysis through RT-PCR in the rat and monkey hypothalamus did notidentify BNP mRNA (Abdelalim et al., 2006; Langub et al., 1995) However,radioimmunoassay studies have detected BNP in porcine (Ueda et al., 1988),canine (Itoh et al., 1989), rat (Sone et al., 1991), human (Takahashi et al., 1992),and ovine (Pemberton et al., 2002) hypothalamus BNP-immunoreactivefibers are also present in the PVN of the hypothalamus and many BNP-positiveneurons have been retrogradely labeled in the tuberomammillary nucleus ofthe hypothalamus and in the pedunculopontine and laterodorsal tegmentalnuclei (Moga and Saper, 1994; Saper et al., 1989) An immunohistochemicalstudy on monkey hypothalamus revealed BNP-like immunoreactivity in theform of clusters of granules in the PVN, SON, and periventricular area(Abdelalim et al., 2006) These BNP-positive dots were located in neurons,

oligodendrocytes, astrocytes, and microglial cells It has been suggested thatBNP granules in the hypothalamus are originated from outside the hypothala-mus and reach the hypothalamus through the subfornical organ (Abdelalim

et al., 2006) as high-density binding sites for BNP have been observed byautoradiography in rat subfornical organ, SON, and paraventricular hypotha-lamic nucleus (Brown and Czarnecki, 1990) and NPR-A mRNA has beenfound in the subfornical organ (Langub et al., 1995)

CNP has also been identified in the human hypothalamus in both high andlow molecular weight forms by using radioimmunoassay (Totsune et al.,1994a) In the ovine hypothalamus, the concentration of CNP is much higherthan that of ANP, similar amounts of CNP-53- and CNP-22-like immunore-active-CNP being present (Yandle et al., 1993) In the rat hypothalamus, thehighest CNP tissue concentrations have been found in the arcuate nucleus andPVN (Herman et al., 1993; Minamino et al., 1993) Hybridization signals oflower intensity were reported in the medial, median, and periventricularpreoptic area; the SON; dorsomedial, ventral premammillary, and lateralmammillary nuclei; and in the posterior hypothalamic area (Herman et al.,1993) Through in situ hybridization, prepro-CNP mRNA has also beendetected in the rat hypothalamus, particularly in the anteromedial preopticnucleus of the medial preoptic area (Ryan et al., 1997) CNP synthesis has alsobeen identified in immortalized luteinizing hormone-releasing hormone(LHRH) neurons using RT-PCR, immunocytochemistry, and electronmicroscopic immunohistochemistry and in these cells CNP also elevatedLHRH production in an autocrine manner (Middendorff et al., 1997) Theconcentration of CNP in the cerebrospinal fluid has been reported to be oneorder of magnitude greater than that of ANP (Kaneko et al., 1993)

Gibson et al (1986) have found the highest levels of ANP binding in therat subfornical organ, area postrema and olfactory apparatus; moderate ANPbinding has been found throughout the brainstem and low levels in theforebrain, diencephalon, basal ganglia, cortex, and cerebellum ANP-bind-ing sites have been identified in hypothalamic and nonhypothalamic struc-tures in both rat and guinea pig (Mantyh et al., 1987) ANP-binding siteshave been identified in cerebral circumventricular organs, including thesubfornical organ and organum vasculosum of the lamina terminalis(Mendelsohn et al., 1987) ANP-binding sites have also been reported inthe SON and in the magnocellular and parvocellular subdivisions of thePVN in rat (Castre´n and Saavedra, 1989) In particular, high numbers ofANP-binding sites have been reported in the circumventricular organs (theorganon vasculosum laminae terminalis, subfornical organum, and areapostrema) and selected hypothalamic (SON, median preoptic, and paraven-tricular) nuclei (Kurihara et al., 1987) ANP-binding sites have also beenreported in the median eminence, pineal gland, subfornical organ, choroidplexus, but not in the magnocellular hypothalamic nuclei (Gerstberger

et al., 1992)

NPR-B mRNA has been observed to be expressed throughout the thalamus, in the magnocellular and parvocellular paraventricular, the arcuate,and the SON, the median preoptic, anteroventral periventricular, tuberomam-millary, ventromedial, and suprachiasmatic nuclei (Langub et al., 1995) Thethree receptors have been identified in astrocyte glial and neuronal culturesfrom the hypothalamus and brain stem of 1-day-old rats, with astrocytescontaining predominantly the ANP-A subtype and neurons predominantlythe ANP-B subtype (Sumners and Tang, 1992) NPR-A and -B mRNA havealso been identified in the GT1-7 cell line, an immortalized LHRH neuronalcell line All the natriuretic peptides elevated cGMP production in this cell linewith the following rank order of potency: CNP > ANP > BNP (Olcese

hypo-et al., 1994) NPR-C expression has also been found in mammalian amus (Peng et al., 1996; Sumners and Tang, 1992) In the human, ovine, andrat hypothalamus, higher expression of CNP and NPR-B have been foundthan of ANP, BNP, and NPR-A (Herman et al., 1993, 1996a; Komatsu et al.,1991; Langub et al., 1995; Minamino et al., 1993; Pemberton et al., 2002).Natriuretic peptide expression in the rat hypothalamus has also beenstudied with reference to postnatal maturation It has been found throughradioimmunoassay that ANP concentrations show a first increase in thepostnatal days 0–5 and a second one in the postnatal days 10–20, for a 16-fold final increase ( Jankowski et al., 2004) Increments of ANP mRNAhave also been found by in situ hybridization in the septohypothalamic,lateral, periventricular, and arcuate nuclei from postnatal day 4 until post-natal days 21–28 (Ryan and Gundlach, 1998) In rat SON and suprachias-matic nuclei, ANP peptide and mRNA have been identified starting fromthe 18th day of the fetal life (Lipari et al., 2005, 2007) CNP concentrations,instead, increased steadily until postnatal day 60, when they were 3.7-foldhigher than at birth ( Jankowski et al., 2004) As regards concentrations ofthe transcripts of the natriuretic peptides receptors in adult versus newbornrats, higher NPR-A concentrations, lower NPR-C concentrations, and nodifferences in NPR-B concentrations were found ( Jankowski et al., 2004)

hypothal-3.2 Pituitary gland

ANP has been identified in the rat anterior pituitary by radioimmunoassay(Gutkowska and Cantin, 1988) and ANP and BNP mRNA have beenidentified in human pituitary by PCR (Gerbes et al., 1994) The presence

of all the three natriuretic peptides has been reported through noassay in the ovine pituitary, CNP (15.84 pmol/g wet weight) showinghigher concentrations than ANP and BNP (0.25 and 0.26 pmol/g wetweight) (Pemberton et al., 2002) In the ovine hypophysis, the CNP-53-like IR-CNP was mainly present (Yandle et al., 1993) CNP has beenidentified by radioimmunoassay in the anterior lobe and neurointermediatelobe of the pituitary (Komatsu et al., 1991) ANP-like immunoreactivity has

radioimmu-been detected in the rat posterior hypophysis (Gutkowska et al., 1987).

In particular, a low molecular weight peptide with a RP-HPLC patternsimilar to that of the synthetic rat 28-amino acid C-terminal (Ser 99-Tyr126) ANP was found, together with an unidentified higher molecularweight peptide (Gutkowska et al., 1987) An immunohistochemical study

on rat pituitary gland has found ANP-, BNP-, and CNP-immunoreactivecells in the anterior lobe but not in the intermediate lobe of fetal andmaternal glands on day 21 of gestation, fetal samples showing fewer andweakly stained cells (Chatelain et al., 2003) ANP has been localized byimmunohistochemistry (Gutkowska and Cantin, 1988; McKenzie et al.,1985) and in situ hybridization (Morel et al., 1989a) in rat gonadotroph cells.Its expression has also been reported through RT-PCR in LbT2 cells andprimary mouse pituitary tissue (Thompson et al., 2009) An in vivo ultra-structural autoradiographic approach through intravenous injection of125

I-ANP has also demonstrated internalization of extracellular ANP bygonadotroph cells (Morel et al., 1989a) BNP has not been found to beexpressed in gonadotrophaT3-1 and LbT2 cells and rat and mouse pitui-taries (Thompson et al., 2009) Conversely, CNP has been localized in ratand mouse LH-positive cells of the anterior pituitary and in aT3-1 andLbT2 cells (McArdle et al., 1994; Thompson et al., 2009) Putative proces-sing enzymes of CNP (Furin and peptidyl a-amidating monoxygenaseenzymes) have also been found to be expressed inaT3-1 cells and primarymouse pituitaries Transcriptional analyses revealed that CNP expression isresponsive to GNRH action in a protein kinase C and calcium-dependentmanner (Thompson et al., 2009) The CNP promoter has been reported towork effectively also in somatomammotroph or somatotroph GH3 cells butnot in corticotroph AtT20 cells (Ohta et al., 1993)

ANP-binding sites have also been reported in the anterior pituitary inrabbit (Gerstberger et al., 1992) and rat (Agui et al., 1989) and in theposterior pituitary in guinea pig (Mantyh et al., 1986) and rabbit(Gerstberger et al., 1992) NPR-A and -B have been isolated from ahuman pituitary cDNA library (Chang et al., 1989; Wilcox et al., 1991)

In situ hybridization study in the anterior pituitary of rhesus monkey hasrevealed NPR-A and NPR-B mRNA (Wilcox et al., 1991) NPR-BmRNA has been identified in some cells of the anterior pituitary and inpituicytes in the neural lobe (Herman et al., 1996a) Northern blot analysisidentified all three natriuretic peptide receptors in the mouse pituitary(Guild and Cramb, 1999) Analysis in alpha T3-1 and AtT-20 cell linesdid not confirm the presence of NPR-A mRNA, suggesting cGMP accu-mulation occurring via NPR-B (Gilkes et al., 1994; McArdle et al., 1994).Ohta et al (1993) have identified NPR-B in rat pituitary somatotroph andsomatolactotroph progenitor cells In situ hybridization in rat anterior pitui-tary gland has revealed NPR-A, -B, and -C mRNA in lactotroph, cortico-troph, and gonadotroph cells, but not in somatotroph or tyreotroph ones

(Grandcle´ment et al., 1995; Thompson et al., 2009) NPR-C mRNA hasbeen identified by in situ hybridization not only in the rat anterior lobe butalso in the intermediate one (Herman et al., 1996b) Pituicytes culturedfrom adult rat neurohypophyses have been found to possess high-affinitybinding sites for ANP, but ANP has been found not to modulate the basal orelectrically stimulated release of OT or vasopressin (VP) from the isolatedneurohypophysis in vitro (Luckman and Bicknell, 1991) NPR-B mRNAhas also been found in the pars intermedia and posterior of the pituitarygland in the monkey (Wilcox et al., 1991) and rat (Konrad et al., 1992).NPR-B mRNA was also observed in the neural lobe of the pituitary gland,suggesting expression by pituicytes (Langub et al., 1995).

3.3 Adrenal cortex

Although Morel et al (1988) did not report the presence of ANP mRNA inthe rat adrenal cortex and Lee et al (1994) did not report BNP mRNA andprotein in the adrenal cortex by in situ hybridization and immunohisto-chemistry, ANP and BNP mRNA have been identified in human adrenalgland (without distinction between cortex and medulla) by PCR (Gerbes

et al., 1994) Moreover, Lai et al (2000) detected ANP mRNA and protein

by in situ hybridization and immunohistochemistry in the rat zona ulosa and outer region of the zona fasciculata, but not in the remaining part

glomer-of the zona fasciculata and in the zona reticularis In bovine, CNP mRNAhas also been demonstrated by RT-PCR in the zona glomerulosa tissue andcultured cells and CNP immunoreactivity has been localized in the outer-most region of the adrenal cortex but not in the inner portion of the zonafasciculata and zona reticularis (Kawai et al., 1996)

ANP-binding sites have been identified in the rat, guinea pig, rabbit,bovine, and tree shrew adrenal zona glomerulosa (e.g., Chai et al., 1986; DeLe´an et al., 1984; Fuchs et al., 1986; Gerstberger et al., 1992; Lynch et al.,1986; Mantyh et al., 1986; Mendelsohn et al., 1987; Morel et al., 1989b) Inparticular, internalization of ANP in rat adrenal glomerulosa cells was alsodemonstrated (Morel et al., 1989b) ANP-binding sites have also beenobserved in the rat zona fasciculata (Chai et al., 1986) and in the treeshrew and bovine zona fasciculata and reticularis (Fuchs et al., 1986;Nunez et al., 1990) Lynch et al (1986) also reported the presence ofANP-binding sites in the rat zona fasciculata and reticularis, although atlower levels Developmental changes have also been reported in the expres-sion of ANP receptors as in the 16-day-old rat ANP-binding sites arepresent throughout the cortical area but at 20 days gestation and 1 daypostpartum ANP receptors are more numerous in the peripheral region(Scott and Jennes, 1989) Conversely, rat adrenocortical autotransplantsregenerated from capsular-tissue fragments implanted in the musculus gra-cilis have been found not to significantly bind 125I-ANP (Belloni et al.,

1993) BNP-binding sites have also been identified in bovine adrenocorticalmembrane fractions (Higuchi et al., 1989).

In the rat zona glomerulosa cells, mRNA of the three natriuretic peptidereceptors have been identified (Grandcle´ment et al., 1997; Nagase et al., 1997;Vaillancourt et al., 1997) The amount of NPR-A mRNA has been found to

be the highest (Grandcle´ment et al., 1997) and Western analysis using clonal anti-NPR-A and anti-NPR-B antibodies revealed the presence ofNPR-A but not of NPR-B proteins (Vaillancourt et al., 1997) Wilcox et al.(1991) reported the presence of NPR-A but not NPR-B in the monkey zonaglomerulosa by in situ hybridization and observed clusters of NPR-C-positivecells suggestive of endothelial, not necessarily secretory, cells In the rat zonafasciculata cells, NPR-A but not NPR-B and -C receptor’s mRNA has beenidentified (Mulay et al., 1995; Vaillancourt et al., 1997) In the monkey zonafasciculata and reticularis, mRNA of the three receptors was not identified insecretory cells (Wilcox et al., 1991) NPR-A has also been identified in theH295R human adrenocortical cell line (Bodart et al., 1996)

poly-Plasma ANP concentrations are known to decrease after water deprivation

or hemorrhage and to increase after blood volume expansion Conversely,data concerning plasma ANP concentrations in response to salt-overloadingare contradictory Water deprivation increases total number of ANP recep-tors in the adrenal gland of adult and maternal rats, but not of fetal ones(Deloof et al., 1999; Lynch et al., 1986) In particular, the density of NPR-Cbut not of NPR-B has been found to be increased (Deloof et al., 1999) Moststudies, with few exceptions (Deloof et al., 2000) reported downregulation ofthe ANP receptors in the adrenal glands after salt-overloading (Lynch et al.,1986; Sessions et al., 1992)

et al., 1998) In situ hybridization identified ANP mRNA in noradrenergic cellswhile immunohistochemistry identified ANP protein in both noradrenergicand adrenergic cells, suggesting ANP synthesis in noradrenergic cells andinternalization in adrenergic ones (Morel et al., 1988) It has also been reportedthat the majority ANP-immunoreactive chromaffin cells are the adrenergicones (Wolfensberger et al., 1995) Electrical stimulation of the splanchnicnerves has been found to cause the release of ANP-like immunoreactivematerial in isolated perfused calf adrenal glands (Duntas et al., 1993; Edwards

et al., 1990) and enhance the uptake of ANP by chromaffin cells (Edwards

et al., 1990)

It has been hypothesized that ANP produced in the adrenal medulla may act

on the adrenal cortex (Lee et al., 1993, 1994; Nawata et al., 1991) and may beinvolved in the regulation of blood flow and even in the zonation of the adrenalcortex (Lee et al., 1994).125I-ANP-binding sites have been identified by in vivoautoradiography in rat adrenal medulla and by in vitro autoradiography inbovine, guinea pig, tree shrew, rabbit, and rat adrenal medulla (Bormann

et al., 1989; Fuchs et al., 1986; Gerstberger et al., 1992; Konrad et al., 1992;Maurer and Reubi, 1986; Morel et al., 1988; Niina et al., 1996) Specificbinding sites for ANP have been identified in the phaeochromocytoma cell linePC12 (Boumezrag et al., 1988) 125I-ANP-binding sites, instead, have notbeen identified in mouse, hamster, monkey, human, and in other studies inbovine, guinea pig, and rat (Chai et al., 1986; Lynch et al., 1986; Mantyh et al.,1986; Maurer and Reubi, 1986; Stewart et al., 1988) In rat, 125I-BNPand125I-[Tyr0]-CNP-binding sites have also been identified (Konrad

et al., 1992) The number of ANP-binding sites has also been found toincrease regularly in fetal (day 17 of gestation and term) and neonatal (weeks

1 and 4) rats (Deloof et al., 1994)

NPR-A and NPR-B mRNA, but not NPR-C mRNA, have been tified by in situ hybridization in adrenal chromaffin cells of monkey (Wilcox

iden-et al., 1991) This finding is in keeping with displacing of 125I-ANPand125I-BNP bindings by ANP and BNP but not by selective analoguesfor NPR-C in rat and bovine (Konrad et al., 1992; Niina et al., 1996) Inrat adrenal medulla, the mRNA of the three subtypes has been found by insitu hybridization, the amount of NPR-A mRNA being the highest(Grandcle´ment et al., 1997) The above receptors were selectively present

in adrenaline-containing chromaffin cells and not in the containing ones (Grandcle´ment et al., 1997)

noradrenaline-NPR-A mRNA expression has also been reported to be significantlyincreased in the adrenal medulla of adult pro-ANP gene-disrupted mice(O’Tierney et al., 2007)

4 Effects of Natriuretic Peptides on the

HPA Axis

4.1 Hypothalamus

ANP has been found to modulate the membrane excitability of neurons of thelateral septal nucleus, lateral paraolfactory area, bed nucleus of the anteriorcommissure, and medial preoptic area (Wong et al., 1986) ANP has beenfound to produce significant increases in blood pressure and heart rate wheninjected into the preoptic suprachiasmatic nucleus, suggesting it may play animportant role in central cardiovascular regulatory mechanisms (reviewed inOparil et al., 1996) Moreover, intracerebroventricular injection of ANP has

been found to inhibit dehydration- and angiotensin II-induced water intake inconscious, unrestrained rats (Antunes-Rodrigues et al., 1985).

ANP, BNP, and CNP have been found to reduce both spontaneous andacetylcholine, Kþand angiotensin II-evoked norepinephrine release in slices ofrat hypothalamus (Giridhar et al., 1992; Vatta et al., 1996) ANP has beenfound to increase neuronal norepinephrine uptake in hypothalamus(Fernandez et al., 1993) and in organum vasculosum lamina terminalis andorganum subfornical (Vatta et al., 1995) of rat BNP and CNP have also beenfound to increase neuronal norepinephrine uptake in slices of rat hypothalamusand, particularly, independently of the hypothalamic nucleus involved (pre-optic, periventricular, paraventricular, SON, and arcuate nuclei; median emi-nence) (Rodriguez Fermepin et al., 2000; Vatta et al., 1996) ANP has beenfound to diminish monoamine oxidase activity, but not catechol-O-methyltransferase activity and the formation of deaminates metabolites, in rat hypo-thalamus slices (Vatta et al., 1998) Moreover, centrally applied ANP has beenreported to increase the hypothalamic content of NE, diminish its utilizationand turnover, inhibit basal and KCl-evoked tyrosine hydroxylase activity, andincrease cyclic GMP levels (Vatta et al., 1999)

Experimental studies on rats have shown that ANP microinjections into thethird ventricle do not change basal levels of OT but attenuate the increase in

OT secretion induced by hyperosmolarity (Chriguer et al., 2001; Gutkowska

et al., 1997; Lewandowska et al., 1992; McCann et al., 1996; Poole et al.,1987) ANP has also been found to markedly inhibit OT release in vitro fromthe isolated neurointermediate lobe both under basal condition as well asduring stimulation (Lewandowska et al., 1992; Poole et al., 1987)

ANP has been proven to be a potent inhibitor of VP neurons of the PVN inanesthetized rats (Okuya and Yamashita, 1987; Standaert et al., 1987) Intrave-nous infusion of ANP has been found to reduce dehydration and hemorrhage-induced VP release in the rat (Samson, 1985) ANP has been reported to inhibitthe basal and stimulated release of VP in hypothalamo-neurohypophyseal slicepreparations and in superfused rat posterior pituitary gland ( Januszewicz et al.,1986; Obana et al., 1985) ANP has also been found to inhibit VP release in vitrofrom the neurointermediate lobes both under basal condition as well as duringstimulation (Lewandowska et al., 1992; Poole et al., 1987) Intracerebroven-tricular injections of ANP, BNP, or CNP have been found to show inhibitoryeffects on the VP secretion (e.g., Iitake et al., 1986; Lewandowska et al., 1992;Makino et al., 1992; Poole et al., 1987; Samson et al., 1991; Shirakami et al.,1993) The three natriuretic peptides have also been reported to inhibit thebasal secretion of VP from rat SON neurons in dissociated cell preparations,CNP being the most potent inhibitory factor (Yamamoto et al., 1997).Reduction of VP plasma levels due to central ANP stimulus has been observed

in both euhydrated and dehydrated sheeps (Lee et al., 1987) and rats(Manzanares et al., 1990) In rats, inhibition of VP secretion was not accom-panied by modifications in the concentrations of 3,4-dihydroxyphenylacetic

acid and dopamine, indicating that ANP-induced suppression of VP secretion

is not mediated by tuberohypophysial or tuberoinfundibular dopaminergicneurons (Manzanares et al., 1990) Conversely, in dehydrated but not ineuhydrated rabbits, infusion of ANP has also been found to inhibit secretion

of VP (Gerstberger et al., 1992) ANP and BNP have also been found todecrease the firing rate and hyperpolarize the membrane potential in phasicallyfiring (putative VP) but not in nonphasically firing (putative OT) neurons ofSON; inhibition of cGMP synthesis was also reported in neurons of SON(Akamatsu et al., 1993) ANP and BNP have been found to inhibit AV3Vneurons, suggesting direct actions of the peptides on drinking, and in the SON,these peptides inhibited selectively putative VP neurons but not putative OTneurons, suggesting direct actions of the peptides on VP secretion (Yamamoto

et al., 1995) The central inhibition of OT and VP release from the cellular neurosecretory cells by ANP has been suggested to be mediated bypresynaptic inhibition of glutamate release from osmoreceptor afferentsderived from the organum vasculosum lamina terminalis (Richard andBourque, 1996) Experiments through injection of highly specific antiserumagainst ANP into the third cerebral ventricle of rats also showed that theinhibitory role in suppressing ACTH release during stress is in part mediated

magno-by inhibition of VP release (Franci et al., 1992) Conversely, it has also beenreported an increase of the plasma VP response to acute moderate hemorrhageafter intracerebroventricular injection of CNP (Charles et al., 1995)

It has also been demonstrated that CNP has a potent and selectiveinhibitory effect on magnocellular cells of SON and PVN, which ismediated by NPR-C (Rose et al., 2005) Moreover, since NPR-C bindsall natriuretic peptides with equal affinity (Levin et al., 1998), it has beensuggested that this receptor could mediate the hypothalamic effects by theother natriuretic peptides (Rose et al., 2005)

It has been reported that intracerebroventricular injection of ANP in ratsdoes not modify tuberoinfundibular dopaminergic neuronal activity and serumprolactin levels, but it attenuates the stimulatory effects of angiotensin II ontuberoinfundibular dopaminergic neuronal activity, negatively modulatingalso the inhibitory effect on serum prolactin level (Yen and Pan, 1997) ANPand BNP have been reported to cause a dose-dependent increase in dopamineaccumulation in cultured rat hypothalamic cells through an increase in intra-cellular cGMP concentration (Kadowaki et al., 1992) Franci et al (1992) alsoreported a role by ANP in augmenting the prolactin release in stress through ahypothalamic action On the other hand, CNP has been found to stimulateprolactin secretion in rats by a hypothalamic site of action (Huang et al., 1992a;Samson et al., 1995)

In rat, ANP has been found to inhibit acetylcholine- and KCl-inducedrelease of corticotrophin-releasing factor in vitro (Grossman et al., 1993;Ibanez-Santos et al., 1990; Takao et al., 1988) and to increase its immuno-reactivity in the hypothalamus in vivo (Biro´ et al., 1996) In humans,

intranasal administration of ANP has been shown to inhibit secretion ofACTH stimulated by hypoglycemia but not by CRH/VP, suggestinginhibition of central nervous mechanisms of HPA activation, probably atthe level of the hypothalamus (Perras et al., 2004) High doses of BNP andCNP have been found to increase and decrease, respectively, corticotropin-releasing factor immunoreactivity in the hypothalamus (Gardi et al., 1997).Charles et al (1992) reported suppression of the adrenocortical secretion inthe sheep after intracerebroventricular injection of CNP, while ANP had

no significant effect The same research group in a following experimentreported increase of the plasma cortisol response to acute moderate hemor-rhage after intracerebroventricular injection of CNP, although the plasmaACTH response was not significantly different, probably for feedbackinhibition (Charles et al., 1995) Intracerebroventricular injections ofBNP and CNP have been found to inhibit the stress-induced corticosteroneresponse, without changes of the basal secretion, thus suggesting a hypotha-lamic actions of these hormones ( Ja´szbere´nyi et al., 1998, 2000) Experi-ments through injection of highly specific antiserum against ANP into thethird cerebral ventricle of rats to immunoneutralize hypothalamic ANPshowed that ANP inhibits basal but not stress-induced GH release Thesame study did not find a modulatory role by ANP in thyroid-stimulatinghormone release (Franci et al., 1992)

ANP and CNP have been reported to inhibit LHRH release (Huang

et al., 1992b; Samson et al., 1992, 1993) Microinjection of antisera againstANP into the third cerebral ventricle of rats produced elevation of plasma

LH levels (Franci et al., 1990) Conversely, some authors reported a slightincrease in LH serum levels after applying ANP into rat PO/AH by means

of push–pull cannula, probably through reduction of preoptic GABArelease rates (Rodriguez Lopez et al., 1993) Recent studies involvingricin A chain conjugated ANP suggest that ANP binding to clearancereceptors in the hypothalamus displaces CNP from the shared clearancereceptor, making more CNP available to inhibit LHRH release throughbinding to the ANPR-B receptor (Samson et al., 1992, 1993) The perfu-sion of hypothalamo-neurohypophysial complex with ANP has also beenfound to increase the beta-endorphin concentration, whereas such an effectwas not reported in isolated neurointermediate lobes of rat pituitary (Ikeda

et al., 1991; Kova´cs and Antoni, 1990) and in vitro (King and Baertschi, 1989;

Kova´cs and Antoni, 1990; Shibasaki et al., 1986b) In cultured ovine and ratanterior pituitary cells, CRF- and VP-stimulated, but not basal, ACTHsecretion has also been found to be inhibited by rat ANP (Dayanithi andAntoni, 1990; Engler et al., 1990) This effect was also confirmed for all threenatriuretic peptides in vitro in mouse hemipituitary preparations over aconcentration range of 10 12 10 10 M (Guild and Cramb, 1999) and

in vivo in humans (Kellner et al., 1992) Inhibition of ACTH release wasaccompanied by stimulation of cGMP accumulation (Guild and Cramb,1999) Conversely, it must also be considered that in the work by Ur et al.(1991) significant differences were not found in mean peak cortisol andACTH levels between ANP and placebo infusion In young healthy menexposed to ANP infusion and stimulation of ACTH secretion by CRH and/

or VP, Bierwolf et al (1998) reported inhibition of ACTH/cortisol secretoryresponses within the first hour after stimulation with secretagogues andaugmentation of ACTH/cortisol response during the third hour after stimu-lation The early suppression was ascribed to direct inhibitory actions of ANP

on both adrenal release of cortisol and pituitary release of ACTH; the lateeffect was ascribed to secondary hypovolemic actions Natriuretic peptideshave been found to stimulate cGMP accumulation in AtT-20 cell line, CNPbeing the most effective hormone (Fowkes and McArdle, 2000), but not toaffect basal or CRF-stimulated ACTH secretion (Gilkes et al., 1992, 1994)

In AtT-20 cells, ANP has also been found to reduce POMC mRNA content,together with a modest reduction in the release and cell content of beta-endorphin-like immunoreactivity (Tan et al., 1994) ANP, BNP, and CNPhave also been reported to inhibit CRF-stimulated ACTH secretion andproopiomelanocortin mRNA expression in in vitro fetal rat pituitary gland inlate gestation (Chatelain et al., 2003) The three natriuretic peptides areequipotent in inhibiting the CRF-stimulated ACTH release (Chatelain

et al., 2003; Guild and Cramb, 1999) Intracerebroventricular administration

of BNP has also been found to suppress endothelin-induced ACTH secretion

in rat (Makino et al., 1990) Other studies, instead, have not reportedinhibition on ACTH secretion by ANP in cultured pituitary cells of rat,sheep, and horse (e.g., Bowman et al., 1997; Mulligan et al., 1997) Horvath

et al (1986) also reported a small but significant stimulation of ACTH release

by ANP in superfused rat pituitary cells Mulligan et al (1997) also reportedabsence of inhibition on ACTH secretion by CNP in horse cultured pituitarycells Such differences may be explained with reference to different in vitromodels or concentrations of ANP

The three natriuretic peptides have been reported to cause increases incGMP content in GH3 cells (McArdle et al., 1993) Experimental studies

on rat pituitary have reported ANP suppression of basal, growth hormonereleasing factor-stimulated and stress-induced GH secretion (Shibasaki et al.,1986b) Conversely, other studies on superfused anterior pituitary cells didnot revealed any effect by ANP on GH release (Horvath et al., 1986;

Shimekake et al., 1994) and central administration of ANP in rats(Murakami et al., 1988) stimulated GH release In other studies, stimulation

of GH release by natriuretic peptides has been reported from rat culturedanterior pituitary cells, such as GH3 cell line, ANP and CNP being the mosteffective hormones (Fowkes and McArdle, 2000; Hartt et al., 1995).Shimekake et al (1994) reported stimulation of GH release by CNP, butnot ANP, from GH3 cells In conclusion, effects of natriuretic peptides on

GH release seem to be equivocal

ANP has been found to produce cGMP accumulation in rat anteriorpituitary cells in culture, basal, and ANP-induced cGMP levels being higher

in cell populations enriched in gonadotrophs compared to impoverished preparations, but alteration of LH release was not reported(Simard et al., 1986) ANP, BNP, and CNP have also been found tostimulate cGMP accumulation in primary cultures of rat pituitary cells andaT3-1 and LbT2 gonadotroph-derived cells, ANP and CNP being themost effective hormones in stimulating LbT2 and aT3-1 cells, respectively(Fowkes and McArdle, 2000; McArdle et al., 1993; Thompson et al., 2009).Moreover,aT3-1 cells produced significantly more cGMP in response toCNP than other cell lines, that is, GH3, TtT-GF, and AfT-20 cells (Fowkesand McArdle, 2000) CNP has been found to inhibit GnRH-stimulatedcalcium mobilization in aT3-1 gonadotroph-derived cells (Fowkes et al.,1999) Moreover, CNP has been reported to stimulate the human glyco-protein hormonea-subunit promoter in LbT2 cells, although not in aT3-1ones (Thompson et al., 2009) However, CNP had no measurable effects onbasal and GnRH-stimulated LH release and on cell proliferation (McArdle

gonadotroph-et al., 1993; Thompson gonadotroph-et al., 2009) Conversely, stimulation of LH andFSH release had been reported by ANP in anterior pituitary cells of rats(Horvath et al., 1986), although recently not confirmed (Thompson et al.,2009) Intracerebroventricular injection of ANP has also been reported toinduce an increase in plasma LH levels without significantly affectingprolactin release (Steele, 1990) On the other hand, Standaert et al.(1986b) had reported in vivo inhibition of the release of LH by ANP

In conclusion, effects of natriuretic peptides on LH and FSH release willhave to be better clarified in the future

ANP has been found not to affect thyrotropin and PRL release fromdispersed rat anterior pituitary cells, but central administration of high doses

in rats has been reported to cause significant inhibition of PRL release(Horvath et al., 1986; Samson and Bianchi, 1988) ANP, BNP, and CNPhave also been found to stimulate cGMP accumulation in TtT-GF cell line, apituitary folliculo-stellate-like cell line derived from an isologously transplan-table pituitary thyrotropic tumor line, CNP being the most effective hormone(Fowkes and McArdle, 2000) Synthetic rat ANP has also been found toattenuate, in a dose-dependent manner, basal and CRF-induced secretion of

proopiomelanocortin-derived peptides from cultured intermediate lobe cells

of rat pituitary (Shibasaki et al., 1986b)

4.3 Adrenal cortex

In the cells of the mammal adrenal zona glomerulosa, ANP has been found toinhibit basal and angiotensin II-, Kþ -, PACAP-, calcium ionophores andACTH-stimulated aldosterone secretion via a cGMP-mediated mechanism(e.g., Atarashi et al., 1984; Bodart et al., 1997; Chartier et al., 1984; Cozza et al.,1993; Deloff et al., 1992; Elliott et al., 1993; Isales et al., 1989; Kudo and Baird,1984–1985; Lotshaw et al., 1991; Mazzocchi et al., 1987; Naruse et al., 1987;Nawata et al., 1991; Nussdorfer et al., 1988–1989; Spiessberger et al., 2009;Vesely et al., 1995; reviewed in Ganguly, 1992; Nussdorfer, 1996) Inhibition

of aldosterone production in adrenal zona glomerulosa cells has also beenreported by a specific ligand for NPR-C (Isales et al., 1992) Inhibition ofangiotensin II-induced aldosterone production by a NPR-A agonist has alsobeen demonstrated in H295R human adrenocortical cell line (Bodart et al.,1996) On the other hand, the pro-ANP 1–30 and 31–67 have been found not

to affect angiotensin II-stimulated aldosterone secretion in calf adrenal cells(Denker et al., 1990) ANP-induced inhibition of aldosterone secretion hasalso been found to be mediated by inhibition of T-type calcium channels(McCarthy et al., 1990) ANP has also been found to diminish cAMP levels inglomerulosa cells through stimulation of a phosphodiesterase by cGMP(MacFarland et al., 1991; Nikolaev et al., 2005; Spiessberger et al., 2009).Moreover, ANP has been found to have no effect on ACTH-stimulatedaldosterone levels in mice with a homozygous inactivation of the cGMP-dependent protein kinase II, suggesting involvement of this enzyme in ANP-mediated inhibition of aldosterone expression (Spiessberger et al., 2009).Inhibition of the phosphorylation of the myristoylated alanine-rich C-kinasesubstrate (MARCKS) and the synthesis and phosphorylation of the steroido-genic acute regulatory protein (StAR) has also been found to play a pivotal role

in inhibition of aldosterone production (Calle et al., 2001; Cherradi et al.,1998) ANP has also been found to inhibit the phosphorylation of histone H3

in bovine adrenal glomerulosa cells (Elliott, 1990)

In cultured human and bovine adrenal cells, BNP has also been found toincrease intracellular cGMP and inhibit ACTH- and angiotensin II-stimulatedaldosterone secretion (Hashiguchi et al., 1989; Higuchi et al., 1989; Nawata

et al., 1991) In calf adrenal zona glomerulosa cells in culture, BNP has alsobeen found to inhibit AII-, Kþ,- and ACTH-stimulated increase in aldoste-rone, while CNP showed only weak effects (Cozza et al., 1993) In bovineadrenal zona glomerulosa cells in culture, CNP has also been found to increasethe basal secretion of cGMP and inhibit ACTH-stimulated increase in aldoste-rone (Kawai et al., 1996) In primary human adrenocortical cells investigatedthrough intracellular cGMP assay and cDNA microarray, BNP has been

reported to induce cGMP synthesis and oppose 49% of ANGII-regulatedgenes, with particular reference to genes involved in cell growth and differen-tiation, steroid synthesis, and cholesterol synthesis and transfer (Liang et al.,2007) Treatment with BNP alone, instead, produced downregulation only of

a small number of genes Moreover, BNP inhibited ANGII-induced tion of the binding of LDL and HDL and of the release of aldosterone, cortisol,and estradiol (Liang et al., 2007)

stimula-ANP has also been reported to inhibit the growth of rat zona glomerulosa(Mazzocchi et al., 1987; Rebuffat et al., 1988; Trejter et al., 2002); this actionhas been reported with both ANP and ANP antagonist, suggesting a non-receptor-mediated mechanism of action (Trejter et al., 2002)

ANP has been found to decrease basal and ACTH-stimulated coid production from cultured human and cow zona fasciculata cells (Carr andMason, 1988; Hashiguchi et al., 1989; Naruse et al., 1987; Nawata et al., 1991).This effect was also observed in the Y1 mouse adrenocortical tumor cell line(Heisler et al., 1989) Other studies did not show effects of ANP on glucocor-ticoid secretion in rat (Cantin and Genest, 1985; Ganguly, 1992) It has alsobeen found that isolated fasciculata cells of rat adrenal cortex, when incubatedwith ANP, stimulated the levels of cyclic GMP and corticosterone production

glucocorti-in a concentration-dependent manner ( Jaiswal et al., 1986) ANP treatment for

6 days has been reported to increase plasma concentrations of cortisol by about20% in normal guinea pigs and by about 3.5-fold in dexamethasone/captopriladministered animals, indicating a direct action on the adrenal gland AlthoughANP has been found not to affect cortisol secretion from dispersed guinea pigzona fasciculata-reticularis cells, a raise in cortisol production has been reported

in guinea pig adrenocortical slices containing adrenomedullary tissue, ing an indirect effect, mediated by medullary chromaffin cells, under thesecretagogue action of ANP (Raha et al., 2006) In fact, the bulk ofevidence indicates that catecholamines are able to stimulate steroidogenesisthrough binding beta-adrenoreceptors on adrenocortical cells (Lightly et al.,1990; Mazzocchi et al., 1998; Nussdorfer, 1996) and various peptides, such

suggest-as neuromedin U (Malendowicz et al., 1994, 2009), VIP and PACAP(Nussdorfer and Malendowicz, 1998a), neuropeptide-Y (Spinazzi et al.,2005), tachykinins (Nussdorfer and Malendowicz, 1998b), endothelins(Malendowicz et al., 1998; Nussdorfer et al., 1999), and adrenomedullin(Nussdorfer, 2001), have been found to stimulate cortisol secretion byindirect action on the medullary chromaffin cells Lastly, in the evaluation

of ANP effects on adrenal gland, relevant species-specific differences must

et al., 1989; Nawata et al., 1991) Many in vitro studies have been performed ontransformed cell lines and different findings in studies performed on cell culturesmay derive from the fact that transformed cell lines may not appropriately reflectthe features of primary human adrenal cells (Liang et al., 2007).

4.4 Adrenal medulla

In the literature, the three natriuretic peptides have been reported toincrease cGMP content in the rat and bovine adrenal chromaffin cells(Ferna´ndez et al., 1997; Fe´thie`re et al., 1993; Tsutsui et al., 1994;Yanagihara et al., 1991) ANP has been reported to inhibit catecholaminerelease by adrenal medulla cells (e.g., Babinski et al., 1995; Ferna´ndez et al.,1997; Papouchado et al., 1995; Vatta et al., 1994; reviewed in Kobayashi

et al., 1998) In particular, ANP has been demonstrated to inhibit choline-induced membrane currents in bovine chromaffin cells (Bormann

acetyl-et al., 1989) and to enhance activity of potassium conductance (Ganz acetyl-et al.,1994) ANP mediates also indirect sympathoinhibitory effects throughantagonism of the renin-angiotensin (Atlas and Maack, 1987) and endothe-lin (Emori et al., 1993; Neuser et al., 1993) systems, which modulatecatecholamine release from the adrenal medulla (Armando et al., 2004;Lange et al., 2000) ANP has also been found to reduce monoamine oxidaseactivity, but not catechol-O-methyl transferase activity and the formation ofdeaminates metabolites, in rat adrenal medulla slices (Vatta et al., 1998)

In cultured bovine adrenal medullary cells ANP increases phosphorylationand activity of tyrosine hydroxylase (Yanagihara et al., 1991), whereas, in ratadrenal medulla, inhibition of both spontaneous and KCl-evoked THactivity has been reported (Ferna´ndez et al., 1997) In rat adrenal medullarycells, ANP has also been found to increase noradrenaline uptake (Vatta et al.,1992) and endogenous content and to diminish noradrenaline utilization(Ferna´ndez et al., 1997) Pro-ANP gene-disrupted mice have also found toshow an increase in circulating catecholamine levels (Melo et al., 1999) andupregulation of tyrosine hydroxylase expression in sympathetic ganglia andadrenal medulla (O’Tierney et al., 2007) Conversely, in some studies ANPhas been found to potentiate catecholamine secretion due to low concentra-tions (3mM) of nicotine in bovine adrenal chromaffin cells (O’Sullivan andBurgoyne, 1990) and to enhance catecholamine release from bovine adre-nomedullary cultured cells of guinea pigs (Raha et al., 2006)

BNP has also been show to stimulate tyrosine hydroxylase activity, incultured adrenomedullary cells (Yanagihara et al., 1991), and to decreasespontaneous and KCl-induced norepinephrine release and enhance nor-adrenaline uptake in rat adrenal medulla slices (Vatta et al., 1996, 1997)

It has been suggested that BNP may contribute to increase adrenal tyrosinehydroxylase expression in ANP/mice due to elevated levels of NPR-A(O’Tierney et al., 2007)

CNP has also been found to inhibit catecholamine secretion stimulated bynicotine (10mM), acetylcholine (50 mM), or KCl (30 mM) in bovine chromaf-fin cells, through cGMP-dependent and -independent mechanisms (Babinski

et al., 1995; Rodriguez-Pascual et al., 1996) Inhibition of spontaneous andKCl-induced catecholamine release has also been demonstrated in rat adrenalmedulla slices, together with enhancement of noradrenaline uptake (Vatta

et al., 1997) CNP has also been reported to stimulate catecholamine synthesis,through increasing of intracellular cGMP content and activation of tyrosinehydroxylase, in cultured bovine adrenal medullary cells (Tsutsui et al., 1994)

5 Natriuretic Peptides and Pathophysiology

of HPA Axis

5.1 Adrenocortical adenomas and carcinomas

Plasma levels of ANP and BNP have been found to be higher in patientswith primary aldosteronism due to aldosterone-producing adrenal adenoma

or bilateral adrenal hyperplasia, reduced levels being found after adenomaresection ( Jakubik et al., 2006; Kato et al., 2005; Lapinski et al., 1991;Naruse et al., 1994; Tunny and Gordon, 1986; Yamaji et al., 1986) BNPwas more closely correlated with blood volume, being a more sensitivemarker of cardiac load or volume status in patients with primary aldoste-ronism (Kato et al., 2005)

In human adrenocortical tumors, CNP has been found by noassay in concentration of 0.69  0.19 pmol/g wet tissue, with respect to0.49  0.22 pmol/g wet tissue in normal adrenal glands (cortex andmedulla mixed) (Totsune et al., 1994b) BNP has been found by radioim-munoassay in concentrations of 0.203  0.061 pmol/g wet tissue in normaladrenal glands (cortex and medulla mixed), 0.230 0.062 pmol/g wettissue in aldosteronomas, and 0.180 0.054 pmol/g wet tissue in adreno-cortical adenomas with Cushing’s syndrome (Totsune et al., 1996) Multi-ple molecular forms of BNP have been reported in aldosteronomas(Totsune et al., 1996) Significant differences in the allelic frequencies ofrestriction fragment length polymorphisms in the ANP gene have beenfound between angiotensin II-unresponsive and -responsive aldosterone-producing tumors (Tunny et al., 1994) Enhanced expressions of ANP andBNP from adrenal medulla surrounding aldosteronomas have also beenreported (Lee et al., 1993, 1994)

radioimmu-The inhibitory effect of natriuretic peptides on aldosterone productionfrom aldosteronomas has been found to be less potent or even absent (Hirata

et al., 1985; Mantero et al., 1987; Naruse et al., 1987; Nawata et al., 1991;Rocco et al., 1989; Shionoiri et al., 1988, 1989) Moreover, ANP has beenfound not to inhibit basal and ACTH-stimulated cortisol secretion in tissue

slices of Cushing’s adenoma (Shionoiri et al., 1989) Shionoiri et al (1988,1989) did not report NPR-A presence in aldosteronoma by binding assayand immunohistochemistry mRNA of the three NPRs has been found inthe aldosteronomas (Chen et al., 1995; Sarzani et al., 1999) NPR-B and -CmRNA, but not NPR-A mRNA, have been reported to be downregulated

in aldosteronomas by Chen et al (1995), while Sarzani et al (1999) did notreport significant differences Moreover, ANP-binding sites have also beenreported to be reduced in aldosteronomas (Ohashi et al., 1991; Sarzani et al.,1999)

5.2 Pheochromocytomas

In patients with pheochromocytoma, higher plasma ANP concentration hasbeen found with respect to controls and patients with essential hypertensionand ANP concentrations has been reported to decline after removal of thetumor, suggesting that catecholamines produced by the chromaffin tumorinduce ANP secretion through stimulation of adrenergic receptors(Stepniakowski et al., 1992) In human pheochromocytomas, BNP andCNP have been found in concentrations of 0.205  0.037 pmol/g wettissue (Totsune et al., 1996) and 0.54  0.40 pmol/g wet tissue, respec-tively (Totsune et al., 1994b) Multiple molecular forms of BNP have beenreported in pheochromocytomas (Totsune et al., 1996)

Nakamaru et al (1989) reported increases in plasma levels of mines after intravenous infusion of ANP in patients with pheochromocy-toma but they did not observe modifications of the basal release ofcatecholamines from isolated superfused pheochromocytoma tissue.Release of catecholamines from tissue slices of pheochromocytoma hasbeen found to be inhibited by hANP in a dose-dependent manner, bindingassays using 125I-ANP have revealed a single class of high-affinity bindingsites for ANP and immunohistochemistry has also revealed the presence ofANP receptors (Shionoiri et al., 1987, 1989)

catechola-6 Concluding Remarks

The preceding sections of the paper have shown that a huge mass ofdata strongly suggests that natriuretic peptides play an important role in theregulation of the function of the HPA axis, although some important topicshave not yet received adequate answers The above data and doubts may besynthesized as follows Natriuretic peptides and their receptors are widelyexpressed in the hypothalamus, although some doubts still remain if BNP islocally expressed or internalized through receptor binding In the hypothal-amus, natriuretic peptides play different roles: reduction of norepinephrine

release; inhibition of OT, VP, corticotropin-releasing factor, growth mone, and LHRH release All the natriuretic peptides and their receptorsare present in the hypophysis; in particular, the three subtypes of receptorsseem to be present in lactotroph, corticotroph, gonadotroph cells, equivocaldata being present regarding somatotroph ones Nevertheless a huge mass ofstudies investigating the effects of natriuretic peptides on pituitary cellpopulations, some doubts are still present Majority of literature (althoughnot all the literature) reported inhibition of both basal and induced ACTHrelease by natriuretic peptides Instead really contrasting data are presentregarding effects of natriuretic peptides on GH, LH, and FSH release, beingreported inhibition, stimulation, or absence of effects in different studies.Such differences may be explained with reference to different in vitro or

hor-in vivo models but surely request further analyses hor-in the future Natriureticpeptides have mainly been identified in the zona glomerulosa and adrenalmedulla They are known to inhibit aldosterone secretion and growth ofzona glomerulosa More problematic are data regarding effects of natriureticpeptides in the zona fasciculata Inhibition or stimulation of glucocorticoidsecretion by adrenocortical cells has been reported and these contradictorydata may be explained with reference to the different species considered.Lastly, in the adrenal medulla, natriuretic peptides inhibit catecholaminerelease and increase catecholamine uptake

Despite the extensive experimental investigations of the natriureticpeptide biology under both normal and pathological conditions manyinteresting problems remain to be addressed in the next years It will have

to be better investigated how the central nervous system control thenatriuretic peptide system in the central and peripheral branches of theHPA axis Moreover, natriuretic peptides modulate different hormonalsystems and further experiments are needed to better ascertain the func-tional interrelationships between these systems Data reviewed inSections 5.1 and 5.2 indicate that the natriuretic peptide system is involved

in the pathophysiology of adrenal cortical and medullary neoplasias butfurther studies will be necessary

The study of these and many other basic topics, along with the ment of new potent and selective agonists and antagonists of the differentreceptors, not only will open new frontiers in the knowledge of thephysiology of the HPA axis, but also will shed light on new therapeuticalperspectives Moreover, in recent years new technologies have been devel-oped which could be used in order to specifically study the expression andaction of natriuretic peptides in the different components of the HPA axis.Laser-capture microdissection has recently been applied to obtain homoge-neous cell populations from nervous and endocrine structures, such as thehypothalamus (Segal et al., 2005) and pituitary gland (Lloyd et al., 2005).Microarray and proteomic analyses have also been performed on mRNAand proteins extracted from these cell populations Laser-capture

microdissection in conjunction with microarray analysis may allowgenome-wide screening of transcripts from homogeneous cell populations

of hypothalamus and pituitary in order to better analyze the expression ofnatriuretic peptides and receptors and to specifically study the effects ofthese peptides on different cell types Microarray and proteomics studiescould also provide complete and accurate profiles of expression in response

to various environmental stimuli

Akamatsu, N., Inenaga, K., Yamashita, H., 1993 Inhibitory effects of natriuretic peptides on

VP neurons mediated through cGMP and cGMP-dependent protein kinase in vitro.

Armando, I., Jezova, M., Bregonzio, C., Baiardi, G., Saavedra, J.M., 2004 Angiotensin II AT1 and AT2 receptor types regulate basal and stress-induced adrenomedullary cate- cholamine production through transcriptional regulation of tyrosine hydroxylase Ann.

renin-in bovrenin-ine chromaffrenin-in cells The regulation of its biosynthesis and secretion FEBS Lett.

313, 300–302.

Babinski, K., Haddad, P., Vallerand, D., McNicoll, N., de Le´an, A., Ong, H., 1995 Natriuretic peptides inhibit nicotine-induced whole-cell currents and catecholamine secretion in bovine chromaffin cells: evidence for the involvement of the atrial natriuretic factor R2 receptors J Neurochem 64, 1080–1087.

Belloni, A.S., Neri, G., Andreis, P.G., Musajo, F.G., Gottardo, G., Mazzocchi, G., et al.,

1993 A comparative study of the effect of atrial natriuretic peptide (ANP) on the secretory activity of rat adrenal cortex and angiotensin-II-responsive adrenocortical autotransplants Exp Toxicol Pathol 45, 341–344.

Bierwolf, C., Burgemeister, A., Luthke, K., Born, J., Fehm, H.L., 1998 Influence of exogenous atrial natriuretic peptide on the pituitary-adrenal response to corticotropin- releasing hormone and vasopressin in healthy men J Clin Endocrinol Metab 83, 1151–1157.

Biro´, E., Gardi, J., Vecsernye´s, M., Julesz, J., To´th, G., Telegdy, G., 1996 The effects of atrial natriuretic peptide (ANP1-28) on corticotropin releasing factor in brain of rats Life Sci 59, 1351–1356.

Bodart, V., Rainey, W.E., Fournier, A., Ong, H., De Le´an, A., 1996 The H295R human adrenocortical cell line contains functional atrial natriuretic peptide receptors that inhibit aldosterone biosynthesis Mol Cell Endocrinol 118, 137–144.

Bodart, V., Babinski, K., Ong, H., De Le´an, A., 1997 Comparative effect of pituitary adenylate cyclase-activating polypeptide on aldosterone secretion in normal bovine and human tumorous adrenal cells Endocrinology 138, 566–573.

Bormann, J., Flugge, G., Fuchs, E., 1989 Effect of atrial natriuretic factor (ANF) on nicotinic acetylcholine receptor channels in bovine chromaffin cells Pflu¨gers Arch.

414, 11–14.

Boumezrag, A., Lyall, F., Dow, J.A., 1988 Characterization of specific binding of atrial natriuretic peptide (ANP) to rat PC12 phaeochromocytoma cells Life Sci 43, 2035–2042.

Bowman, M.E., Robinson, P.J., Smith, R., 1997 Atrial natriuretic peptide, cyclic GMP analogues and modulation of guanylyl cyclase do not alter stimulated POMC peptide release from perifused rat or sheep corticotrophs J Neuroendocrinol 9, 929–936 Brown, J., Czarnecki, A., 1990 Autoradiographic localization of atrial and brain natriuretic peptide receptors in rat brain Am J Physiol 258, R57–R63.

Calle, R.A., Bollag, W.B., White, S., Betancourt-Calle, S., Kent, P., 2001 ANPs effect on MARCKS and StAR phosphorylation in agonist-stimulated glomerulosa cells Mol Cell Endocrinol 177, 71–79.

Cantin, M., Genest, J., 1985 The heart and the atrial natriuretic factor Endocr Rev 6, 107–127.

Carr, B.R., Mason, J.I., 1988 The effects of alpha-human atrial natriuretic polypeptide on steroidogenesis by fetal zone cells of the human fetal adrenal gland Am J Obstet Gynecol 159, 1361–1365.

Castre´n, E., Saavedra, J.M., 1989 Lack of vasopressin increases hypothalamic atrial uretic peptide binding sites Am J Physiol 257, R168–R173.

natri-Chai, S.Y., Sexton, P.M., Allen, A.M., Figdor, R., Mendelsohn, F.A.O., 1986 In vivo autoradiographic localization of ANP receptors in rat kidney and adrenal gland Am J Physiol 250, F753–F757.

Chang, M.S., Lowe, D.G., Lewis, M., Hellmiss, R., Chen, E., Goeddel, D.V., 1989 Differential activation by atrial and brain natriuretic peptides of two different receptor guanylate cyclases Nature 341, 68–72.

Charles, C.J., Richards, A.M., Espiner, E.A., 1992 Central C-type natriuretic peptide but not atrial natriuretic factor lowers blood pressure and adrenocortical secretion in normal conscious sheep Endocrinology 131, 1721–1726.

Charles, C.J., Espiner, E.A., Richards, A.M., Donald, R.A., 1995 Central C-type uretic peptide augments the hormone response to hemorrhage in conscious sheep Peptides 16, 129–132.

Chartier, L., Schiffrin, E., Thibault, G., Garcia, R., 1984 Atrial natriuretic factor inhibits the stimulation of aldosterone secretion by angiotensin II, ACTH and potassium in vitro and angiotensin II-induced steroidogenesis in vivo Endocrinology 115, 2026–2028 Chatelain, D., Lesage, J., Montel, V., Chatelain, A., Deloof, S., 2003 Effect of natriuretic peptides on in vitro stimulated adrenocorticotropic hormone release and pro-opiomela- nocortin mRNA expression by the fetal rat pituitary gland in late gestation Horm Res.

Cherradi, N., Brandenburger, Y., Rossier, M.F., Vallotton, M.B., Stocco, D.M., Capponi, A.M., 1998 Atrial natriuretic peptide inhibits calcium-induced steroidogenic acute regulatory protein gene transcription in adrenal glomerulosa cells Mol Endocri- nol 12, 962–972.

Chriguer, R.S., Rocha, M.J., Antunes-Rodrigues, J., Franci, C.R., 2001 Hypothalamic atrial natriuretic peptide and secretion of oxytocin Brain Res 889, 239–242.

Cozza, E.N., Foecking, M.F., Vila, M.C., Gomez-Sanchez, C.E., 1993 Adrenal receptors for natriuretic peptides and inhibition of aldosterone secretion in calf zona glomerulosa cells in culture Acta Endocrinol 129, 59–64.

Dagnino, L., Drouin, J., Nemer, M., 1991 Differential expression of natriuretic peptide genes in cardiac and extracardiac tissues Mol Endocrinol 5, 1292–1300.

Dayanithi, G., Antoni, F.A., 1990 Atriopeptins are potent inhibitors of ACTH secretion by rat anterior pituitary cells in vitro: involvement of the atrial natriuretic factor receptor domain of membrane-bound guanylyl cyclase J Endocrinol 125, 39–44.

De Le´an, A., Gutkowska, J., McNicoll, N., Schiller, P.W., Cantin, M., Genest, J., 1984 Characterization of specific receptors for atrial natriuretic factor in bovine adrenal zona glomerulosa Life Sci 35, 2311–2318.

De Le´an, A., Ong, H., McNicoll, N., Racz, K., Gutkowska, J., Cantin, M., 1985 cation of aldosterone secretion inhibitory factor in bovine adrenal medulla Life Sci.

J Endocrinol 142, 524–532.

Deloff, S., Lepreˆtre, A., Montel, V., Chaˆtelain, A., 1992 Effect of rat atrial natriuretic factor

on in vivo and in vitro aldosterone and corticosterone secretions in the rat during the perinatal period Biol Neonate 62, 145–154.

Denker, P.S., Vesely, D.L., Go´mez-Sa´nchez, C.E., 1990 Effect of pro-atrial natriuretic peptides 1-30, 31-67 and 99-126 on angiotensin II-stimulated aldosterone production in calf adrenal cells J Steroid Biochem Mol Biol 37, 617–619.

Duntas, L., Bornstein, S.R., Scherbaum, W.A., Holst, J.J., 1993 Atrial natriuretic like immunoreactive material (ANP-LI) is released from the adrenal gland by splanchnic nerve stimulation Exp Clin Endocrinol 101, 371–373.

peptide-Edwards, A.V., Ghatei, M.A., Bloom, S.R., 1990 The effect of splanchnic nerve stimulation

on the uptake of atrial natriuretic peptide by the adrenal gland in conscious calves.

J Endocrinol Invest 13, 887–892.

Elliott, M.E., 1990 Phosphorylation of adrenal histone H3 is affected by angiotensin, ACTH, dibutyryl cAMP, and atrial natriuretic peptide Life Sci 46, 1479–1488 Elliott, M.E., Goodfriend, T.L., Jefcoate, C.R., 1993 Bovine adrenal glomerulosa and fasciculata cells exhibit 28.5-kilodalton proteins sensitive to angiotensin, other agonists, and atrial natriuretic peptide Endocrinology 133, 1669–1677.

Emori, T., Hirata, Y., Imai, T., Eguchi, S., Kanno, K., Marumo, F., 1993 Cellular mechanism of natriuretic peptides-induced inhibition of endothelin-1 biosynthesis in rat endothelial cells Endocrinology 133, 2474–2480.

Engler, D., Pham, T., Liu, J.P., Fullerton, M.J., Clarke, I.J., Funder, J.W., 1990 Studies of the regulation of the hypothalamic-pituitary-adrenal axis in sheep with hypothalamic- pituitary disconnection II Evidence for in vivo ultradian hypersecretion of proopiome- lanocortin peptides by the isolated anterior and intermediate pituitary Endocrinology

127, 1956–1966.

Fernandez, B.E., Vatta, M.S., Bianciotti, L.G., 1993 Comparative effects of bradykinin and atrial natriuretic factor on neuronal and non-neuronal noradrenaline uptake in the central nervous system of the rat Arch Int Physiol Biochim Biophys 101, 337–340 Ferna´ndez, B.E., Leder, M., Ferna´ndez, G., Bianciotti, L.G., Vatta, M.S., 1997 Atrial natriuretic factor modifies the biosynthesis and turnover of norepinephrine in the rat adrenal medulla Biochem Biophys Res Commun 238, 343–346.

Fe´thie`re, J., Graihle, R., Larose, L., Babinski, K., Ong, H., De Le´an, A., 1993 Distribution and regulation of natriuretic factor-R1C receptor subtypes in mammalian cell lines Mol Cell Biochem 124, 11–16.

Fink, G., Dow, R.C., Casley, D., Johnston, C.I., Lim, A.T., Copolov, D.L., et al., 1991 Atrial natriuretic peptide is a physiological inhibitor of ACTH release: evidence from immunoneutralization in vivo J Endocrinol 131, R9–R12.

Fowkes, R.C., McArdle, C.A., 2000 C-type natriuretic peptide: an important crine regulator? Trends Endocrinol Metab 11, 333–338.

neuroendo-Fowkes, R.C., Forrest-Owen, W., Williams, B., McArdle, C.A., 1999 C-type natriuretic peptide (CNP) effects on intracellular calcium [Ca2þ]i in mouse gonadotrope-derived alphaT3-1 cell line Regul Pept 84, 43–49.

Franci, C.R., Anselmo-Franci, J.A., McCann, S.M., 1990 Opposite effects of central immunoneutralization of angiotensin II or atrial natriuretic peptide on luteinizing hor- mone release in ovariectomized rats Neuroendocrinology 51, 683–687.

Franci, C.R., Anselmo-Franci, J.A., McCann, S.M., 1992 The role of endogenous atrial natriuretic peptide in resting and stress-induced release of corticotropin, prolactin, growth hormone, and thyroid-stimulating hormone Proc Natl Acad Sci USA 89, 11391–11395.

Fuchs, E., Shigematsu, K., Saavedra, J.M., 1986 Binding sites of atrial natriuretic peptide in tree shrew adrenal gland Peptides 7, 873–876.

Ganguly, A., 1992 Atrial natriuretic peptide-induced inhibition of aldosterone secretion:

a quest for mediator(s) Am J Physiol 263, E181–E194.

Ganz, M.B., Nee, J.J., Isales, C.M., Barrett, P.Q., 1994 Atrial natriuretic peptide enhances activity of potassium conductance in adrenal glomerulosa cells Am J Physiol 266, C1357–C1365.

Gardi, J., Bı´ro´, E., Vecsernye´s, M., Julesz, J., Nya´ri, T., To´th, G., et al., 1997 The effects of brain and C-type natriuretic peptides on corticotropin-releasing factor in brain of rats Life Sci 60, 2111–2117.

Gardner, D.G., Vlasuk, G.P., Baxter, J.D., Fiddes, J.C., Lewicki, J.A., 1987 Identification of atrial natriuretic factor gene transcripts in the central nervous system of the rat Proc Natl Acad Sci USA 84, 2175–2179.

Gerbes, A.L., Dagnino, L., Nguyen, T., Nemer, M., 1994 Transcription of brain natriuretic peptide and atrial natriuretic peptide genes in human tissues J Clin Endocrinol Metab.

78, 1307–1311.

Gerstberger, R., Schu¨tz, H., Luther-Dyroff, D., Keil, R., Simon, E., 1992 Inhibition of vasopressin and aldosterone release by atrial natriuretic peptide in conscious rabbits Exp Physiol 77, 587–600.

Gibson, T.R., Wildey, G.M., Manaker, S., Glembotski, C.C., 1986 Autoradiographic localization and characterization of atrial natriuretic peptide binding sites in the rat central nervous system and adrenal gland J Neurosci 6, 2004–2011.

Gilkes, A.F., MacKay, K.B., Cramb, G., Guild, S.B., 1992 Atrial natriuretic peptide effects

in AtT-20 pituitary tumour cells Mol Cell Endocrinol 89, 39–45.

Gilkes, A.F., Ogden, P.H., Guild, S.B., Cramb, G., 1994 Characterization of natriuretic peptide receptor subtypes in the AtT-20 pituitary tumour cell line Biochem J 299, 481–487.

Giridhar, J., Peoples, R.W., Isom, G.E., 1992 Modulation of hypothalamic norepinephrine release by atrial natriuretic peptide: involvement of cyclic GMP Eur J Pharmacol 213, 317–321.

Glembotski, C.C., Wildey, G.M., Gibson, T.R., 1985 Molecular forms of immunoactive atrial natriuretic peptide in the rat hypothalamus and atrium Biochem Biophys Res Commun 129, 671–678.

Grandcle´ment, B., Brisson, C., Bayard, F., Tremblay, J., Gossard, F., Morel, G., 1995 Localization of mRNA coding for the three subtypes of atrial natriuretic factor (ANF) receptors in rat anterior pituitary gland cells J Neuroendocrinol 7, 939–948.

Grandcle´ment, B., Ronsin, B., Morel, G., 1997 The three subtypes of atrial natriuretic peptide (ANP) receptors are expressed in the rat adrenal gland Biol Cell 89, 29–41 Grossman, A., Costa, A., Navarra, P., Tsagarakis, S., 1993 The regulation of hypothalamic corticotropin-releasing factor release: in vitro studies Ciba Found Symp 172, 129–150 Guild, S.B., Cramb, G., 1999 Characterisation of the effects of natriuretic peptides upon ACTH secretion from the mouse pituitary Mol Cell Endocrinol 152, 11–19 Gundlach, A.L., Knobe, K.E., 1992 Distribution of preproatrial natriuretic peptide mRNA

in rat brain detected by in situ hybridization of DNA oligonucleotides: enrichment in hypothalamic and limbic regions J Neurochem 59, 758–761.

Gutkowska, J., Racz, K., Debinski, W., Thibault, G., Garcia, R., Kuchel, O., Cantin, M., Genest, J., 1987 An atrial natriuretic factor-like activity in rat posterior hypophysis Peptides 8, 461–465.

Gutkowska, J., Cantin, M., 1988 Bioactive atrial natriuretic factor-like peptides in rat anterior pituitary Can J Physiol Pharmacol 66, 270–275.

Gutkowska, J., Antunes-Rodrigues, J., McCann, S.M., 1997 Atrial natriuretic peptide in brain and pituitary gland Physiol Rev 77, 465–515.

Hartmann, M., Skryabin, B.V., Mu¨ller, T., Gazinski, A., Schro¨ter, J., Gassner, B., et al.,

2008 Alternative splicing of the guanylyl cyclase-A receptor modulates atrial natriuretic peptide signaling J Biol Chem 283, 28313–28320.

Hartt, D.J., Ogiwara, T., Ho, A.K., Chik, C.L., 1995 Cyclic GMP stimulates growth hormone release in rat anterior pituitary cells Biochem Biophys Res Commun 214, 918–926.

Hashiguchi, T., Higuchi, K., Ohashi, M., Takayanagi, R., Matsuo, H., Nawata, H., 1989 Effect of porcine brain natriuretic peptide (pBNP) on human adrenocortical steroido- genesis Clin Endocrinol 31, 623–630.

Hashimoto, K., Hattori, T., Suemaru, S., Sugawara, M., Takao, T., Kageyama, J., et al.,

1987 Atrial natriuretic peptide does not affect corticotropin-releasing factor-, arginine vasopressin- and angiotensin II-induced adrenocorticotropic hormone release in vivo or

in vitro Regul Pept 17, 53–60.

Heisler, S., Tallerico-Melnyk, T., Yip, C., Schimmer, B.P., 1989 Y-1 adrenocortical tumor cells contain atrial natriuretic peptide receptors which regulate cyclic nucleotide metab- olism and steroidogenesis Endocrinology 125, 2235–2243.

Herman, J.P., Langub Jr., M.C., Watson Jr., R.E., 1993 Localization of C-type natriuretic peptide mRNA in rat hypothalamus Endocrinology 133, 1903–1906.

Herman, J.P., Dolgas, C.M., Rucker, D., Langub Jr., M.C., 1996a Localization of uretic peptide-activated guanylate cyclase mRNAs in the rat brain J Comp Neurol.

natri-369, 165–187.

Herman, J.P., Dolgas, C.M., Marcinek, R., Langub Jr., M.C., 1996b Expression and glucocorticoid regulation of natriuretic peptide clearance receptor (NPR-C) mRNA

in rat brain and choroid plexus J Chem Neuroanat 11, 257–265.

Higuchi, K., Hashiguchi, T., Ohashi, M., Takayanagi, R., Haji, M., Matsuo, H., et al., 1989 Porcine brain natriuretic peptide receptor in bovine adrenal cortex Life Sci 44, 881–886 Hirata, Y., Tomita, M., Yoshimi, H., Kuramochi, M., Ito, K., Ikeda, M., 1985 Effect of synthetic human atrial natriuretic peptide on aldosterone secretion by dispersed aldoste- rone-producing adenoma cells in vitro J Clin Endocrinol Metab 61, 677–680 Horvath, J., Ertl, T., Schally, A.V., 1986 Effect of atrial natriuretic peptide on gonadotropin release in superfused rat pituitary cells Proc Natl Acad Sci USA 83, 3444–3446 Huang, F.L.S., Skala, K.D., Samson, W.K., 1992a C-type natriuretic peptide stimulates prolactin secretion by a hypothalamic site of action J Neuroendocrinol 4, 593–597 Huang, F.L.S., Skala, K.D., Samson, W.K., 1992b Hypothalamic effects of C-type natri- uretic peptide on luteinizing hormone secretion J Neuroendocrinol 4, 325–330 Ibanez-Santos, J., Tsagarakis, S., Rees, L.H., Besser, G.M., Grossman, A., 1990 Atrial natriuretic peptides inhibit the release of corticotrophin-releasing factor-41 from the rat hypothalamus in vitro J Endocrinol 126, 223–228.

Iitake, K., Share, L., Crofton, J.T., Brooks, D.P., Ouchi, Y., Blaine, E.H., 1986 Central atrial natriuretic factor reduces vasopressin secretion in the rat Endocrinology 119, 438–440.

Ikeda, Y., Tanaka, I., Oki, Y., Ikeda, Y., Yoshimi, T., 1989 Effect of atrial natriuretic peptide on the release of beta-endorphin from rat hypothalamo-neurohypophysial com- plex Endocrinol Jpn 36, 647–653.

Isales, C.M., Bollag, W.B., Kiernan, L.C., Barrett, P.Q., 1989 Effect of ANP on sustained aldosterone secretion stimulated by angiotensin II Am J Physiol 256, C89–C95 Isales, C.M., Lewicki, J.A., Nee, J.J., Barrett, P.Q., 1992 ANP-(7-23) stimulates a DHP- sensitive Ca2þ conductance and reduces cellular cAMP via a cGMP-independent mechanism Am J Physiol 263, C334–C342.

Itoh, H., Nakao, K., Saito, Y., Yamada, T., Shirakami, G., Mukoyama, M., et al., 1989 Radioimmunoassay for brain natriuretic peptide (BNP) detection of BNP in canine brain Biochem Biophys Res Commun 158, 120–128.

Jaiswal, N., Paul, A.K., Jaiswal, R.K., Sharma, R.K., 1986 Atrial natriuretic factor tion of cyclic GMP levels and steroidogenesis in isolated fasciculata cells of rat adrenal cortex FEBS Lett 199, 121–124.

regula-Jakubik, P., Janota, T., Widimsky Jr., J., Zelinka, T., Strauch, B., Petrak, O., et al., 2006 Impact of essential hypertension and primary aldosteronism on plasma brain natriuretic peptide concentration Blood Press 15, 302–307.

Jankowski, M., Marcinkiewicz, M., Bouanga, J.C., Gutkowska, J., 2004 Changes of atrial natriuretic peptide in rat supraoptic neurones during pregnancy J Neuroendocrinol 16, 441–449.