Clinical Science (1992) 83, 519-527 (Printed in Great Britain)
519
Editorial Review
Atrial and brain natriuretic peptides: a dual natriuretic peptide system potentially involved in circulatory homeostasis Chim C. LANG, Anna-Maria J. CHOY and Allan D. STRUTHERS Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School. Dundee, U.K.
(Fig. 1). It is worth noting that the C-terminal tail commonly found in ANP and BNP is completely lost in the case of CNP. Progress with BNP research is proving extremely rapid and a picture is being built up for BNP which has elements that are similar and elements that are able 1). These recent d here, suggest that BNP and ANP act in a dual natriuretic peptide system intimately involved in circulatory homeostasis.
INTRODUCTION
The discovery of atrial natriuretic peptide (ANP) by de Bold et al. in 1984 [l] has led inevitably to a search for other peptides with natriuretic activity. This search has led to two major new peptides: brain natriuretic peptide (BNP), isolated from both brain and heart [2, 31, and C-type natriuretic peptide (CNP), purified from porcine brain [4]. Like ANP, both of these peptides can elicit vasorelaxant, natriuretic and diuretic responses in chick and rat bioassay systems [2, 41. These natriuretic peptides share a common structural motif consisting of a 17-amino acid loop formed by an intramolecular disulphide linkage. Only five of the 17 amino acids in the ring differ among the three peptides isolated from the pig, whereas the N- and C-terminals vary in both amino acid composition and length [2, 41 (a1
A-rlpe B-type
S-L-R-R-S-S S-P-K-T-M-R-D-S-G
C-type
G-L-S-K-G
a4NP
STRUCTURE, LOCATION AND BIOSYNTHESIS
BNP was first isolated from the porcine brain and has either 26 or 32 amino acid residues, porcine BNP-26 and porcine BNP-32, respectively [Z, 51.
G-R-M
-S-F-R- -Y
a-ANP
R-R-L
-V-L-R-R-Y
BNP-32 CNP
L-K-L
BNP-32
CNP
Fig. 1. Strueturn of ANP, BNP and CNP. (a) Amino acid sequences of porcine CNP, BNP-32 and a-ANP using standard one-letter amino acid notation. Intramolecular disulphide linkage is formed between two cysteine residues in each peptide. Identical residues among the three peptides are shaded. (6) Schematic representation of porcine a-ANP, BNP-32 and CNP structures. Identical residues among the thre$ peptides are indicated by open circles. Reproduced from Sudoh et al. [4] (with permission). I
Key wordm atrial natriuretic peptide, brain natriuretic peptide, blood presrure, congestive heart failure, sodium excretion. , adrenacorticotropichormone; ANP, atrial natriuretic peptide; BNP, bnin natriuretic peptide; cDNA, complementary DNA; CHF, chronic heart failure; natriuretic peptide; ir, immunoreaaive; mRNA, m harmacology, Ninewells Hapita1 and Medical School, Dundee DDI 9SY, U.K. C. C. Lang, Defiartment of Pharmacology
C. C. Lang et al.
520
Table 1. Comparison of A N P and B N P Similarities
Partial similarities
Dissimilarities
Biological activity Inhibition of angiotensin ll-induced water intake and vasopressin secretion Natriuretic Vasorelwant Cyclic GMP effect Aldosteronesuppressive effect
Gene characteristics Amino acid sequences Processing of precunors Receptor populations stimulated
Site of synthesis/secretion Species variation Regional distribution within the central nervous system Clearance halClives Sites of cleavage by endopeptidase24.1I Plasma levels in control subjects and patients with CHF Enhanced natriuretic effect in patients with CHF
The full sequence of BNP has now been elucidated in the pig [6, 71. Rat BNP, a 45-amino acid residue peptide, has also been isolated from the heart [8, 91. Until recently, information on BNP in man has been scarce, mainly because human BNP immunoreactivity was not detected with early antisera which were raised against porcine or rat BNP. However, the complementary DNA (cDNA) sequence encoding for the BNP precursor in man, human BNP (1-108), was recently elucidated [lo]. Since then BNP has been isolated from the human atrium and found to comprise 32 amino acid residues, which are identical with the sequence (77-108) of the human BNP precursor [3, lo]. These peptides, derived from the C-terminus of the pro-BNP molecule, show remarkable similarity to the structure of ANP (99-126), particularly the ring structure formed in these peptides by disulphide bridges (Fig. 2). It is worth noting that the amino acid sequence of BNP may vary as much as 50% among different species, in striking contrast with ANP where the structure is highly conserved between species [l 11. A pattern is gradually being built up of the location of BNP within the body. Naturally enough the central nervous system was the main focus of attention, and Ueda et al. [12] have compared the concentration of immunoreactive (ir) BNP and irANP in the porcine brain. These results, shown in Table 2, reveal marked differences between the location of BNP and ANP in the central nervous system. Overall, there is 13 times more BNP than ANP in the porcine brain, with its highest concentration in the medulla-pons, striatum and spinal cord. This differential localization of BNP and ANP in the brain has been confirmed immunohistochemically [13]. A comparison of the distribution of BNP-containing neurons with the localization of brain BNP-binding sites was performed by Saper et al. [13] and revealed that in many of the examined brain areas there was a correlation between the distribution of BNP-containing neurons and BNP-binding sites, e.g. in the cerebral cortex, hippocampus, olfactory bulb, subfornical organ, paraventricular nucleus, mammilary nucleus, raphe nuclei, locus coeruleus, nucleus of the solitary tract and area postrema. However, as in the case of other
I
BNP-26 (brain) BNP-32 (brain)
.
(4
Fig. 2. BNPs. (a) Porcine BNP. The %amino acid form from brain was the first BNP peptide to be isolated [2]. Later, a 32-amino acid peptide was isolated [S]. A pro-hormone of 106 amino acids, prcBNP, was isolated from the porcine heart [30]. Arrowheads indicate the cleavage sites by renal cortical endopeptidase 24.11 [52]. (b) Rat BNP [9] and (c) human BNP [lo] were both isolated from the heart.
neuropeptides, a mismatch between the distribution of BNP-containing neurons and receptors was observed as well, e.g. in the hypoglossal and periventricular hypothalmic nuclei. Several interpretations have been proposed to justify the phenomenon of receptor-neuropeptide mismatch [14]. An interesting one is that the brain is an endocrine organ, where neuropeptide may be synthesized at one locus and released from another, while acting elsewhere in the brain, the communica-
Brain natriuretic peptide and circulatory homeostasis Table 1. Dl.tribl!tioll of iraNP and irANP ill the porcille celltral "erYOli••y.tllll1. Reproduced from Ueda et 01. [12] (With perml$$ion).
Spinal cord Whole brain Medulla-pons Striatum Hypothalamus Midbrain-thalamus Cortex Olfactory bulb Cerebellum Septum Hippocampus
ir-BNP (pmoljg wet wt.)
ir-ANP (pmoljg wet Wt.)
1.81 0.63 1.59 1.44 1.13 0.51 0.50 0.44 0.09 1.03 0.31
0.06 0.05 0.14
519
Editorial Review
Atrial and brain natriuretic peptides: a dual natriuretic peptide system potentially involved in circulatory homeostasis Chim C. LANG, Anna-Maria J. CHOY and Allan D. STRUTHERS Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School. Dundee, U.K.
(Fig. 1). It is worth noting that the C-terminal tail commonly found in ANP and BNP is completely lost in the case of CNP. Progress with BNP research is proving extremely rapid and a picture is being built up for BNP which has elements that are similar and elements that are able 1). These recent d here, suggest that BNP and ANP act in a dual natriuretic peptide system intimately involved in circulatory homeostasis.
INTRODUCTION
The discovery of atrial natriuretic peptide (ANP) by de Bold et al. in 1984 [l] has led inevitably to a search for other peptides with natriuretic activity. This search has led to two major new peptides: brain natriuretic peptide (BNP), isolated from both brain and heart [2, 31, and C-type natriuretic peptide (CNP), purified from porcine brain [4]. Like ANP, both of these peptides can elicit vasorelaxant, natriuretic and diuretic responses in chick and rat bioassay systems [2, 41. These natriuretic peptides share a common structural motif consisting of a 17-amino acid loop formed by an intramolecular disulphide linkage. Only five of the 17 amino acids in the ring differ among the three peptides isolated from the pig, whereas the N- and C-terminals vary in both amino acid composition and length [2, 41 (a1
A-rlpe B-type
S-L-R-R-S-S S-P-K-T-M-R-D-S-G
C-type
G-L-S-K-G
a4NP
STRUCTURE, LOCATION AND BIOSYNTHESIS
BNP was first isolated from the porcine brain and has either 26 or 32 amino acid residues, porcine BNP-26 and porcine BNP-32, respectively [Z, 51.
G-R-M
-S-F-R- -Y
a-ANP
R-R-L
-V-L-R-R-Y
BNP-32 CNP
L-K-L
BNP-32
CNP
Fig. 1. Strueturn of ANP, BNP and CNP. (a) Amino acid sequences of porcine CNP, BNP-32 and a-ANP using standard one-letter amino acid notation. Intramolecular disulphide linkage is formed between two cysteine residues in each peptide. Identical residues among the three peptides are shaded. (6) Schematic representation of porcine a-ANP, BNP-32 and CNP structures. Identical residues among the thre$ peptides are indicated by open circles. Reproduced from Sudoh et al. [4] (with permission). I
Key wordm atrial natriuretic peptide, brain natriuretic peptide, blood presrure, congestive heart failure, sodium excretion. , adrenacorticotropichormone; ANP, atrial natriuretic peptide; BNP, bnin natriuretic peptide; cDNA, complementary DNA; CHF, chronic heart failure; natriuretic peptide; ir, immunoreaaive; mRNA, m harmacology, Ninewells Hapita1 and Medical School, Dundee DDI 9SY, U.K. C. C. Lang, Defiartment of Pharmacology
C. C. Lang et al.
520
Table 1. Comparison of A N P and B N P Similarities
Partial similarities
Dissimilarities
Biological activity Inhibition of angiotensin ll-induced water intake and vasopressin secretion Natriuretic Vasorelwant Cyclic GMP effect Aldosteronesuppressive effect
Gene characteristics Amino acid sequences Processing of precunors Receptor populations stimulated
Site of synthesis/secretion Species variation Regional distribution within the central nervous system Clearance halClives Sites of cleavage by endopeptidase24.1I Plasma levels in control subjects and patients with CHF Enhanced natriuretic effect in patients with CHF
The full sequence of BNP has now been elucidated in the pig [6, 71. Rat BNP, a 45-amino acid residue peptide, has also been isolated from the heart [8, 91. Until recently, information on BNP in man has been scarce, mainly because human BNP immunoreactivity was not detected with early antisera which were raised against porcine or rat BNP. However, the complementary DNA (cDNA) sequence encoding for the BNP precursor in man, human BNP (1-108), was recently elucidated [lo]. Since then BNP has been isolated from the human atrium and found to comprise 32 amino acid residues, which are identical with the sequence (77-108) of the human BNP precursor [3, lo]. These peptides, derived from the C-terminus of the pro-BNP molecule, show remarkable similarity to the structure of ANP (99-126), particularly the ring structure formed in these peptides by disulphide bridges (Fig. 2). It is worth noting that the amino acid sequence of BNP may vary as much as 50% among different species, in striking contrast with ANP where the structure is highly conserved between species [l 11. A pattern is gradually being built up of the location of BNP within the body. Naturally enough the central nervous system was the main focus of attention, and Ueda et al. [12] have compared the concentration of immunoreactive (ir) BNP and irANP in the porcine brain. These results, shown in Table 2, reveal marked differences between the location of BNP and ANP in the central nervous system. Overall, there is 13 times more BNP than ANP in the porcine brain, with its highest concentration in the medulla-pons, striatum and spinal cord. This differential localization of BNP and ANP in the brain has been confirmed immunohistochemically [13]. A comparison of the distribution of BNP-containing neurons with the localization of brain BNP-binding sites was performed by Saper et al. [13] and revealed that in many of the examined brain areas there was a correlation between the distribution of BNP-containing neurons and BNP-binding sites, e.g. in the cerebral cortex, hippocampus, olfactory bulb, subfornical organ, paraventricular nucleus, mammilary nucleus, raphe nuclei, locus coeruleus, nucleus of the solitary tract and area postrema. However, as in the case of other
I
BNP-26 (brain) BNP-32 (brain)
.
(4
Fig. 2. BNPs. (a) Porcine BNP. The %amino acid form from brain was the first BNP peptide to be isolated [2]. Later, a 32-amino acid peptide was isolated [S]. A pro-hormone of 106 amino acids, prcBNP, was isolated from the porcine heart [30]. Arrowheads indicate the cleavage sites by renal cortical endopeptidase 24.11 [52]. (b) Rat BNP [9] and (c) human BNP [lo] were both isolated from the heart.
neuropeptides, a mismatch between the distribution of BNP-containing neurons and receptors was observed as well, e.g. in the hypoglossal and periventricular hypothalmic nuclei. Several interpretations have been proposed to justify the phenomenon of receptor-neuropeptide mismatch [14]. An interesting one is that the brain is an endocrine organ, where neuropeptide may be synthesized at one locus and released from another, while acting elsewhere in the brain, the communica-
Brain natriuretic peptide and circulatory homeostasis Table 1. Dl.tribl!tioll of iraNP and irANP ill the porcille celltral "erYOli••y.tllll1. Reproduced from Ueda et 01. [12] (With perml$$ion).
Spinal cord Whole brain Medulla-pons Striatum Hypothalamus Midbrain-thalamus Cortex Olfactory bulb Cerebellum Septum Hippocampus
ir-BNP (pmoljg wet wt.)
ir-ANP (pmoljg wet Wt.)
1.81 0.63 1.59 1.44 1.13 0.51 0.50 0.44 0.09 1.03 0.31
0.06 0.05 0.14
