The Many Uses of Natriuretic Peptides

Archana Gangakhedkar Senior Marketing Manager BioVision

ANP, BNP, and CNP are proving to be reliable biomarkers for a variety of conditions.

Natriuretic peptides mainly consist of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), and they belong to the family of endogenous polypeptide mediators of cardiac origin. The term natriuresis means discharge of sodium through urine and is known to have vasodilatory effects. All the three peptides are circulatory hormones of cardiac origin secreted by plasma, with half-lives of around 1 minute and 30 seconds. ANP and BNP hormones act at the site of their synthesis and also circulate in the body. Out of these three hormones, CNP is least secreted with low circulating levels. Increase in sodium loads, extracellular volumes and distension of auricles and ventricles increases the secretion of ANP and BNP.1

ANP, BNP, and CNP are closely related and have a characteristic 17 amino acid residue ring structure formed by an intramolecular disulfide bridge between two cysteine residues. The amino- and carboxyl terminal tails vary between the different peptides, leading to polypeptides of 28 amino acids (ANP), 32 amino acids (BNP), and 53 amino acids (CNP). They also exist as a pro-hormone with a relatively high molecular weight that is cleaved before release into the circulation.2 Both ANP and BNP function through a natriuretic receptor, which generates cyclic-GMP (guanosine mono phosphate) to produce vasodilation and natriuresis.

ANP

ANP is a cardiac hormone involved in the physiological maintenance of blood volume and arterial blood pressure.3 In lab experiments, introduction of the ANP gene to increase the endogenous plasma levels has been used to treat experimental forms of hypertension. Other peptides in the natriuretic peptide family, BNP and CNP, have hypotensive actions similar to ANP although CNP lacks significant natriuretic activity.

ANP release increases in patients with ischemic left ventricular dysfunction. ANP, atrial natriuretic factor, atrial natriuretic hormone, cardionatrin, cardiodilatin, or atriopeptin are polypeptide hormones secreted by heart muscle cells. These hormones are powerful vasodilators and are known to play important role in balancing the levels of body water, sodium, potassium, and adipose tissue. These hormones are released by heart muscle cells in the upper chamber of the heart in response to high blood pressure. The loads of water, sodium, and adipose levels into the circulatory system are reduced by ANP, which functions exactly the opposite of aldosterone, secreted by the zona glomerulosa.

Inside of the heart, cardiac myocytes are responsible for production, storage, and release of ANP. Kim et al., demonstrated that GLP-1R activation promotes the secretion of ANP and a reduction of blood pressure.4

Patients with pulmonary hypertension have elevated concentration of ANP. Reports have also shown a positive correlation between plasma ANP and PAP (pulmonary artery pressure) in patients with different types of congenital heart disease.5

A clinical study in Finland concluded that low levels of mid-regional ANP and N-terminal pro-BNP predicted development of type 2 diabetes. Decreased levels of natriuretic peptides are signs of insulin resistance such as in obesity. Low natriuretic peptide levels lead to faster blood glucose progression over time and predict the development of diabetes in healthy subjects.6 Though it is well known that there is a reduced level of natriuretic peptides in individuals with obesity and diabetes, recently published data7 also shows low levels of natriuretic peptides in people with polycystic ovary syndrome.

Structure of atrial natriuretic peptide (ANP) (1-28) alpha (human, ovine, canine).

BNP

Brain natriuretic peptide, also known as B-type natriuretic peptide (also BNP), is a 32-amino acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells (cardiomyocytes). Circulating levels of BNP-proBNP are normally very low in healthy individuals. In response to increased myocardial wall stress due to volume- or pressure-overload states (such as in heart failure), the BNP gene is activated in cardiomyocytes. The release of BNP is modulated by calcium ions. It has been demonstrated that this peptide has a great pathophysiological importance in diagnosing heart failure8 as well as in risk stratification and guiding heart failure therapy.

BNP has known effects on kidneys, vascular vessels, the endocrine system, and the heart. The earliest findings on BNP were in its effects on the increase on glomerular filtration rate, renal plasma flow, and urine flow rate with inhibition of distal sodium reabsorption. Another important function is BNP may relax myocardium and vascular smooth muscle, causing arterial and venous dilation, which in turn leads to blood pressure reduction and ventricular preload release9. BNP is not only taken as a cardiac biomarker but also a surrogate marker of heart failure, acute coronary syndrome, and myocardial infarction.

Multiple studies have documented the clinical usefulness of BNP and proBNP for diagnosis, prognosis, and treatment of congestive heart failure and for risk stratification in patients with acute coronary syndrome.

Natrecor (nesiritide), from Johnson & Johnson’s subsidiary Scios, was approved in 2001 for treatment of acutely decompensated congestive heart failure. It is a recombinant form of human BNP.

Structure of the 32 residue peptide nesiritide, a recombinant human protein.

CNP

CNP is a 22 amino acid peptide, but unlike ANP and BNP, CNP does not have direct natriuretic activity as CNP is a selective agonist for the B-type natriuretic receptor, whereas ANP and BNP are selective for the A-type natriuretic receptor.

CNP, the third of the natriuretic peptide family, is known to be distributed primarily in the central nervous system and is believed to act as a neuropeptide in contrast to ANP and BNP, which act as cardiac hormones. It has been demonstrated that ANP-B receptor is activated by CNP, which is present not only in the CNS but also in peripheral tissues including blood vessels. The evidence presented in one paper by S. Suga et al.,10 demonstrates the endothelial production of CNP, and the presence of natriuretic receptors in vascular SMC (smooth muscle cells) and EC (endothelial cells) suggest the possible existence of vascular natriuretic peptides.

Research has also shown the presence of CNP receptors in the retinal pigment epithelium (RPE) of the eye, and CNP protects the RPE against advanced glycation end product-induced barrier dysfunction.11 A new report suggests CNP possesses renoprotective properties and is present in kidneys, but its modulation during aging is not known. CNP levels decline with aging and urinary CNP levels increase with aging. This urinary-to-plasma levels CNP ratio can be a novel biomarker for renal fibrosis.

C-type natriuretic peptide (CNP) is a 22 amino acid peptide distributed primarily in the central nervous system.

Summary

The natriuretic peptide family plays a distinct physiological and pathophysiological role in cardiovascular control. It consists of at least four ligands—ANP, BNP, CNP, and DNP (dendroaspis natriuretic peptide)—and three types of receptors expressed in target tissues with tissue specificity. The prognostic use, as well as the therapeutic monitoring value, of BNP measurements is instrumental in preventing incidence of heart failure and other heart diseases.

Archana Gangakhedkar is a technical marketing specialist at American Peptide Company.

References: 1 Toshio Nishikimi et al., Cardiovasc Res (2006); 69 (2): 318-328. 2 Marc Vanderheyden et al., Eur J Heart Fail (2004); 6 (3): 261-268. 3 John R. Dietz; Cardiovasc Res (2005); 68 (1): 8-17. 4 Minsuk Kim et al., Nature Medicine (2013); 19, 567–575. 5 Jingdong Ding et al., cardiovascular Ultrasound (2008); 6, 35. 6 Martin Magnusson et.al, Journal of clinical endocrinology and metabolism, 2012; 97 (2) 638–645. 7 Patricia B. M. Lauria, et al., J Clin Endocrin Metab September 20, 2013 as doi:10.1210/jc.2013-2141. 8 Peter A. McCullough et al., Circulation (2002); 106: 416-422. 9 Nan Li et al., J Zhejiang Univ Sci B. 2005; 6(9): 877–884. 10 S. Suga et al., J Clin Invest. (1992); 90(3): 1145–1149. 11 Ashton Acton, Natriuretic Peptides-Advances in Research and Application. 2013 edition Scholarly Brief.