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

Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types. They are regulated by diverse extracellular agonists that include peptide hormones, bacterial toxins, and free radicals, as well as intracellular molecules, such as calcium and adenine nucleotides. Stimulation of guanylyl cyclases and the resultant accumulation of cGMP regulates complex signaling cascades through immediate downstream effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. Guanylyl cyclases and cGMP-mediated signaling cascades play a central role in the regulation of diverse (patho)physiological processes, including vascular smooth muscle motility, intestinal fluid and electrolyte homeostasis, and retinal phototransduction. Topics addressed in this review include the structure and chromosomal localization of the genes for guanylyl cyclases, structure and function of the members of the guanylyl cyclase family, molecular mechanisms regulating enzymatic activity, and molecular sequences coupling ligand binding to catalytic activity. A brief overview is presented of the downstream events controlled by guanylyl cyclases, including the effectors that are regulated by cGMP and the role that guanylyl cyclases play in cell physiology and pathophysiology.

Guanylyl Cyclases and Signaling by Cyclic GMP

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.

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

A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats

Study objective – The aim was to study the interactions between pulmonary capillary wedge pressure (an estimate of left atrial pressure), left atrial dimension, and atrial natriuretic factor during evolving heart failure.

Design – Sequential simultaneous measurements of haemodynamic variables, left atrial dimension, and plasma atrial natriuretic factor concentrations were obtained during evolving experimental pacing induced heart failure.

Experimental material – Eight male mongrel dogs were paced (250 beats·min−1) to severe heart failure over 4.9(SD 1.8) weeks.

Measurements and results – The development of heart failure was characterised by a progressive increase in pulmonary capillary wedge pressure and left atrial cross sectional area, from 5.6(1.3) mm Hg and 7.9(1.2) cm2 respectively at control, to 25.3(4.9) mm Hg and 14.2(2.5) cm2 respectively (both p<0.01) at severe heart failure. In contrast to the progressive increase in pulmonary capillary wedge pressure and left atrial area, plasma atrial natriuretic factor concentration increased from 98(51) ng·litre−1 at control to a peak of 422(110) ng·litre−1 (p<0.01) at 1 week, then plateaued and reached 354(108) ng·litre−1 at severe heart failure (p<0.05 v control). Plasma atrial natriuretic factor correlated with pulmonary capillary wedge pressure and left atrial area at 1 week (r = 0.73, r = 0.71 respectively, both p<0.0l), but not at the time of severe heart failure.

Conclusion – The divergent time course of the changes in plasma atrial natriuretic factor concentration, pulmonary capillary wedge pressure, and left atrial dimension suggests that in this model, the release of atrial natriuretic factor becomes attenuated as severe heart failure develops.

A. J. De Bold

Papers

A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats

Pathophysiological role of changing atrial size and pressure in modulation of atrial natriuretic factor during evolving experimental heart failure.