Natriuretic Peptides

Definition
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 (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP) 1.

Discovery
De Bold et al reported the first direct evidence of natriuretic substance in 19812. They found that the IV injection of atrial, but not ventricular, homogenates into rats elicited a rapid decrease in blood pressure that was accompanied by increased renal sodium and water excretion. After this seminal observation, several groups purified peptides of varying sizes from atrial tissue that possess both natriuretic and smooth muscle-relaxing activity. These peptides were given a number of different names such as ANP, cardionatrin, cardiodilatin, atriopeptin, and the first description is most often used today. BNP, which was originally called brain natriuretic peptide and CNP were subsequently purified from porcine brain extracts based on their ability to relax smooth muscle.

Structural Characteristics
The natriuretic peptides are a family of ring shaped vasoactive hormones showing considerable sequence homology. All three members contain the conserved sequence CFGXXXDRIXXXXGLGC where X is any amino acid. The flanking cysteines form a 17-amino-acid disulfide-linked ring that is required for biological activity. All natriuretic peptides are synthesized as preprohormones. Human preproANP is 151 amino acids in length. Cleavage of the amino terminal signal sequence results in the 126-amino-acid proANP, which is the predominant form stored in atrial granules. ProANP is rapidly cleaved upon secretion by the transmembrane cardiac serine protease called corin to form the biologically active carboxyl-terminal 28-amino-acid peptide. Human BNP is synthesized as a preprohormone of 134 residues containing a signal sequence that is cleaved to yield a 108-amino-acid prohormone. Additional cleavage by an unknown protease results in an inactive 76-residue amino-terminal fragment and a 32-residue carboxyl-terminal biologically active peptide. CNP is the most conserved natriuretic peptide. Human proCNP contains 103 residues, and the intracellular endoprotease furin has been shown to process proCNP to the mature 53-amino-acid peptide in vitro. In some tissues, CNP-53 is cleaved to CNP-22 by an unknown extracellular enzyme. CNP-53 is the major form in the brain, endothelial cells, and heart, whereas CNP-22 predominates in human plasma and cerebral spinal fluid1.

Mode of Action
Natriuretic peptides elicit their physiological responses through the synthesis of cGMP, a classic intracellular second messenger. There are three known natriuretic peptide binding proteins in mammals: NPR-A, NPR-B, and NPR-C. They are also known as GC-A, GC-B, and the clearance receptor, or as NPR1, NPR2, and NPR3, respectively. NPR-A and NPR-B represent two of the five transmembrane guanylyl cyclases found in humans. The third natriuretic peptide receptor, NPR-C, does not possess any known intrinsic enzymatic activity.

Hypothetical model for NPR-A and NPR-B activation and desensitization:

Three states of receptor activation are labeled "basal," "active," and "desensitized." In the basal state, NPR-A and NPR-B are higher ordered oligomers. In the basal state, they are phosphorylated on five (NPR-B) or six (NPR-A) known sites within the kinase homology domain. It is hypothesized that phosphorylation "licenses" the receptor for hormonal activation. Natriuretic peptide (NP) binding to the highly phosphorylated, inactive basal receptor induces a conformational change that brings eventually brings about the dimerization of guanylyl cyclase domains. Prolonged ligand exposure stimulates receptor dephosphorylation, which results in reduced activity via a process called desensitization. The dephosphorylation primarily results from inhibition of the phosphorylation process. Release of ligand and rephosphorylation returns the enzyme to its basal state1.

Functions
Natriuretic peptides are often described simply as peptides involved in the regulation of blood pressure and volume. However, the effects of these peptides are widespread, and their levels change in response to a variety of pathological conditions.

Effects of the ANP/NPR-A system on blood pressure:

Although ANP was initially suggested to regulate blood pressure in a salt-sensitive manner, more recent data suggest that this is not the case. Its combined effects on intravascular volume, vasorelaxation, natriuresis, and diuresis mediate the hypotensive nature of ANP.

Effects of ANP and BNP on cardiac hypertrophy and fibrosis:

ANP and BNP have direct effects on the heart. Recent evidence suggests that the cardiac fibrosis involves matrix metalloproteinases (MMPs) which are in turn regulated by both ANP and BNP. Several reports indicate that the ANP/BNP/NPR-A system inhibits pressure-induced cardiac remodeling as well.

Effects of ANP on natriuresis and diuresis:

In the kidney, ANP increases glomerular filtration rate, inhibits sodium and water reabsorption, and reduces renin secretion.

Effects of CNP on vascular relaxation and remodeling:

The ability of the cardiac natriuretic peptides to relax precontracted aortic rings requires NPR-A. CNP relaxes aortic rings by a process that does not require NPR-A, presumably by activating NPR-B.

Effects of natriuretic peptides in the lung:

All three natriuretic peptide receptors are highly expressed in the lung. ANP stimulates the dilation of pulmonary airways and blood vessels. Infusion or inhalation of ANP stimulates bronchodilation in normal and asthmatic patients. CNP also reduces pulmonary hypertension and fibrosis.

ANP-dependent antagonism of the renin-aldosterone system:

ANP regulates blood pressure, in part, through the inhibition of the renin-angiotensin II-aldosterone system.

Effects of ANP on fat metabolism:

ANP-stimulated lipolysis is specific to primates presumably because primates contain a higher NPR-A to NPR-C ratio.

Neurological effects of natriuretic peptides:

All natriuretic peptides and natriuretic peptide receptors have been found in the brain, although CNP and NPR-B appear to be particularly abundant. Consistent with the systemic volume-depleting effects, injection of ANP into the third ventricle of the hypothalamus inhibits water intake induced by overnight dehydration or angiotensin II exposure.

Immunological effects of natriuretic peptides:

Natriuretic peptides and their receptors are found in many immune cells. Current evidence suggests a role for ANP in the allergen response of asthma and in immune-related post ischemic damage.

The CNP/NPR-B/cGMP/PKGII system and long bone growth:
The most obvious physiological effect of CNP is to stimulate long bone growth. It regulates many types of bone cells, but its major target appears to be the chondrocyte1.

Therapeutic applications of natriuretic peptides:

BNP and N-terminal-proBNP have become important diagnostic tools for assessing patients who present acutely with dyspnea. Natriuretic peptide levels have important prognostic value in multiple clinical settings, including in patients with stable coronary artery disease and with acute coronary syndromes. In patients with decompensated heart failure due to volume overload, a treatment-induced drop in wedge pressure is often accompanied by a rapid drop in NP levels3.

References
1.Lincoln R. Potter, Sarah Abbey-Hosch and Deborah M. Dickey(2006). Natriuretic Peptides, Their Receptors, and Cyclic Guanosine Monophosphate-Dependent Signaling Functions. Endocrine Reviews, 27(1):47-72.
2.de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H (1981). A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci., 28(1):89-94.
3.Daniels LB, Maisel AS (2007). Natriuretic Peptides. J Am Coll Cardiol., 50(25):2357-2368.