Atrial natriuretic peptide (ANP), a hormone secreted from mammalian atria, regulates the homoeostatic balance of body fluid and blood pressure. ANP-like immunoreactivity is also present in the brain, suggesting that the peptide functions as a neuropeptide. We report here identification in porcine brain of a novel peptide of 26 amino-acid residues, eliciting a pharmacological spectrum very similar to that of ANP, such as natriuretic-diuretic, hypotensive and chick rectum relaxant activities. The complete amino-acid sequence determined for the peptide is remarkably similar to but definitely distinct from the known sequence of ANP, indicating that the genes for the two are distinct. Thus, we have designated the peptide 'brain natriuretic peptide' (BNP). The occurrence of BNP with ANP in mammalian brain suggests the possibility that the physiological functions so far thought to be mediated by ANP may be regulated through a dual mechanism involving both ANP and BNP.

A new natriuretic peptide in porcine brain

The cardiocytes of mammalian cardiac atria contain granules very similar to those in endocrine cells1,2. The number of these atrial granules is related directly to salt loading and blood volume3. Furthermore, crude extracts of rat atria and granule preparations have powerful natriuretic and diuretic effects4,5. These effects are mediated by peptides identified previously as atrial natriuretic factor (ANF). The peptides are derived from a common precursor, whose structure has been elucidated recently6–15. Although there is indirect evidence from morphological studies that at least some of these peptides may be released into the blood and function as hormones, their presence in the blood has not yet been demonstrated. Here we describe a sensitive and specific radio-immunoassay for ANF and its stimulation on volume loading.

Atrial natriuretic factor—a circulating hormone stimulated by volume loading

Purification and complete amino acid sequence of α-human atrial natriuretic polypeptide (α-hANP)

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(03)13976-1.pdf

B-type natriuretic peptide in cardiovascular disease

Natriuretic peptides are a family of structurally related but genetically distinct hormones/paracrine factors that regulate blood volume, blood pressure, ventricular hypertrophy, pulmonary hypertension, fat metabolism, and long bone growth. The mammalian members are atrial natriuretic peptide, B-type natriuretic peptide, C-type natriuretic peptide, and possibly osteocrin/musclin. Three single membrane-spanning natriuretic peptide receptors (NPRs) have been identified. Two, NPR-A/GC-A/NPR1 and NPR-B/GC-B/NPR2, are transmembrane guanylyl cyclases, enzymes that catalyze the synthesis of cGMP. One, NPR-C/NPR3, lacks intrinsic enzymatic activity and controls the local concentrations of natriuretic peptides through constitutive receptor-mediated internalization and degradation. Single allele-inactivating mutations in the promoter of human NPR-A are associated with hypertension and heart failure, whereas homozygous inactivating mutations in human NPR-B cause a form of short-limbed dwarfism known as acromesomelic dysplasia type Maroteaux. The physiological effects of natriuretic peptides are elicited through three classes of cGMP binding proteins: cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. In this comprehensive review, the structure, function, regulation, and biological consequences of natriuretic peptides and their associated signaling proteins are described.

/pdf/natriuretic-peptides-their-receptors-and-cyclic-guanosine-mm2sqziu0p.pdf

Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

Neuromedin K: A novel mammalian tachykinin identified in porcine spinal cord

Recent identification of natriuretic-diuretic activity in peptides isolated from human and rat atrial tissue implicates them in the control of extracellular fluid volume and electrolytic homeostasis. The presence of multiple forms of the peptides ranging from 3,000 to 13,000 molecular weight (MW) suggests they may all derive from the same precursor. The established amino acid sequence of alpha-human atrial natriuretic polypeptide (alpha- hANP ), a 28-residue peptide with potent natriuretic activity, provided the means to elucidate the structure of the precursor for alpha- hANP and the gene encoding it. Here we report the cloning and sequence analysis of the cDNA of human atrial mRNA encoding a precursor of alpha- hANP . The cDNA encodes gamma-human atrial natriuretic polypeptide (gamma- hANP ) of 13,000 MW, whose C-terminal 28 amino acid residues may be processed as alpha- hANP .

Cloning and sequence analysis of cDNA encoding a precursor for human atrial natriuretic polypeptide.

Diuretic and smooth muscle-relaxing peptides, designated atrial natriuretic peptides (ANPs), have been identified in human and rat atrial tissues and implicated in the control of fluid volume and vascular function. Recently, cDNAs encoding the human and rat ANP precursors have been sequenced. We previously isolated from human tissue a natriuretic peptide of molecular weight (MW) 13,000 (gamma-hANP) comprising 126 amino acid residues, the largest natriuretic peptide so far identified, and showed that it is directly derived from the 151-residue human ANP precursor by the removal of a signal peptide. We now report the isolation and sequence analysis of a novel rat atrial natriuretic peptide (gamma-rANP) of MW 13,000, which derives from the rat ANP precursor. We also report the molecular cloning and nucleotide sequence analysis of the cDNA of the 152-residue rat ANP precursor, which is remarkably similar to the human 151-residue precursor (pre-hANP) except at the C-terminus. Differences in the rat and human precursor nucleotide sequences around the termination codons lead to a difference in processing pattern.

Identification of rat γ atrial natriuretic polypeptide and characterization of the cDNA encoding its precursor

Atrial natriuretic polypeptides (ANPs) of varying chain length have been identified recently in human1 and rat2–8 atrial tissue. Their potent natriuretic–diuretic activities indicate their key role in the regulation of extracellular fluid volume and electrolyte balance. Furthermore, human9 and rat10–12 cDNAs encoding their precursor have been cloned and identified. Natriuretic–diuretic activity in human atrial extract comprises three distinct components (α, relative molecular mass (Mr) ∼ 3,000; β, Mr ∼ 6,000; γ, Mr ∼ 13,000) 1. However, only the 3,000-Mr peptide, α-human atrial poly peptide (α-hANP), comprising 28 amino acids, has so far been identified1. We report here the purification and sequence analysis of two novel hANPs of higher Mr, β- and γ-hANP, both of which exhibit natriuretic and hypotensive activity. γ-hANP, composed of 126 amino acids, carries the α-hANP sequence at its carboxy terminus. The identification of γ-hANP reveals that the peptide, being the largest form of hANP, is processed directly from a 151-residue precursor9 by removal of a 26-residue signal peptide. In contrast, β-hANP (56 residues) comprises an anti-parallel dimer of α-hANP; such a dimeric peptide possessing bioactivity has never been found in the tissue as an endogenous entity.

Ayako Fukuda

Papers

Neuromedin K: A novel mammalian tachykinin identified in porcine spinal cord

Cloning and sequence analysis of cDNA encoding a precursor for human atrial natriuretic polypeptide.

Identification of rat γ atrial natriuretic polypeptide and characterization of the cDNA encoding its precursor

Structural identification of β- and γ-human atrial natriuretic polypeptides

Neuromedin L: A novel mammalian tachykinin identified in porcine spinal cord