The atrial natriuretic peptide, ANP, is produced, stored, and released mainly by the cardiac myocytes of the heart’s atrium. A similar system is operative for the release of the “basic” natriuretic peptide (BNP) by the ventricles of the heart. In each instance an elevated vascular volume results in a stretching of the heart’s atrium and ventricles, which initiates the cleavage and secretion, respectively, of both ANP and BNP from the heart.

The several biological effects of ANP (see Table 1) includes inhibition of angiotensin II stimulation of aldosterone biosynthesis, stimulation of the renal glomerulosa filtration rate (GFR) so as to promote Na+ natriuresis, and vasorelaxation. All of these biological effects are individually mediated by the appropriate peptide hormone (ANP, BNP, or CNP) binding to their partner receptor protein (Natriuretic Peptide Receptor, NPR). As shown in Figure 1C, three distinct receptors (NPR-A, NPR-B and NPR-C) have been identified through recombinant, DNA techniques.

Table1. Physiological Actions of Atrial Natriuretic Peptide

Fig1. Structural organization of the atrial natriuretic peptides, their receptors and their biological responses. (A) Amino acid sequences of ANP, BNP, and CNP. The translation of the three color codes for the atrial natriuretic peptides is as follows. The blue color represents the atrial natriuretic peptide (ANP) that is secreted by the human myocytes of the cardiac atrial portion of the heart; this is the reference peptide for the other amino acid sequences. The red color is the B-type natriuretic peptide (BNP) that is produced by both the human brain and the cardiac ventricles; the relative contributions of the two sources of BNP are not clear. The green color is the C-type natriuretic peptide (CNP). Each of the three natriuretic peptides is the product of a separate human gene transcript. The extent of the homology of the peptide sequences of BNP and CNP with the reference ANP can be judged by the position and number of the blue residues present in the red residues of BNP and in the green residues of CNP. Both BNP and CNP have precisely the same homology of 12–13 amino acid residues with ANP. Some evidence supports the view that BNP reduces ventricular fibrosis which is the abnormal thickening of heart valves. (B) Conversion of the linear amino acid sequences of ANP, BNP, and CNP into a circular structure created by a disulfide bond. All three natriuretic peptides are characterized by the presence of a 17-member amino acid ring formed by a disulfide bridge between two cysteine residues. (C) Ligand specificity of ANP, BNP, and CNP for binding to three classes of receptor. Schematic diagram of the interaction of atrial natriuretic peptide hormones binding to their receptors to generate initiation of biological responses. Panel C presents a schematic overview of the structural details of the three families of atrial natriuretic receptors. Both the NPR-A and NPR-B receptor proteins, but not the NPR-C receptor, are comprised of two identical receptor amino acid sequences (of 1037 amino acids) that are only covalently linked together inside the cell (see the blue and green boxes). The extracellular domains have 450 amino acid residues, a hydrophobic membrane spanning region (~21 amino acid residues), and an intracellular domain (566 amino acid residues). The intracellular portion of the receptor protein is divided into three distinct domains: (a) a 250 amino acid kinase homology domain (see blue ovals with several attached phosphates); (b) a 41 amino acid hinge-dimerization region; and (c) a 250 amino acid C-terminal guanylyl cyclase enzyme catalytic domain (see green boxes). In contrast, two NPR-C receptors form a dimer (via a disulfide bond) outside the cell. The NPR-C has a highly truncated intracellular peptide of only~80 amino acid residues and consequently has no catalytic guanylyl cyclase units. Definition of abbreviations: ANP, atrial natriuretic peptide; BNP, basic natriuretic peptide and/or brain natriuretic peptide; CNP, C-type natriuretic peptide; GFR, glomerular filtration rate; FF, fractional flow; UNaV, urinary sodium volume; UV, urinary volume; SNA, sympathetic nervous activity; VSM cell growth; vascular smooth muscle cell growth. (D) Atrial natriuretic hormones secreted by the heart and the wide sphere of action of their biological responses. ANP and BNP are true circulating hormones. They are released from the heart’s atria and ventricles into the circulatory system where they are taken up by the kidney. There are a variety of responses. These include inhibition of renin secretion, and also inhibition of the zona glomerulosa stimulating of aldosterone biosynthesis. ANP increases the glomerular filtration rate as well as the amount of Na+ excretion in the urine. The capillaries experience an increase in permeability when exposed to ANP, thereby increasing the flow of blood. Abbreviations: FF, filtration fraction; GFR, glomerular filtration rate; SNA, sympathetic nervous activity; UNaV, urine sodium excretion; UV, urine volume, VSM, vascular smooth muscle. Abstracted from M.T. Rademaker & E. Espiner in The Endocrine Heart. In K.L. Becker, Ed.; Principles and Practice of Endocrinology and Metabolism, 3rd ed., Philadelphia 2001, Lippincott Williams & Wilkens.

Figure 1C presents a schematic overview of the structural details of the three families of atrial natriuretic receptors. The NPR-A and NPR-B receptors are comprised of two identical receptor amino acid sequences (of 1037 amino acids) that are only covalently linked together inside the cell. Both the NPR-B and NPR-A receptor proteins, but not the NPR-C receptor, span the cell’s plasma membrane and therefore have an extracellular portion (450 amino acid residues), a hydrophobic membrane spanning region (~21 amino acid residues), and an intracellular domain (566 amino acid residues). The intracellular portion of the receptor protein is divided into three dis tinct domains: (a) a 250 amino acid kinase homology domain (see blue ovals with 3– 4 attached phosphates; (b) a 41 amino acid hinge-dimerization region; and (c) a 250 amino acid C- terminal guanylyl cyclase enzyme catalytic domain. The two receptor peptide chains interact only on the inside of the cell to form a dimer (see the schematic green “box”) which are characteristic of catalytic guanylyl cyclase units. In contrast, the NPR-C receptors form a dimer (via a disulfide bond) outside the cell. The NPR-C has a highly truncated intracellular peptide of only ~80 amino acid residues and consequently has no catalytic guanylyl cyclase units.

The NPR-A, NPR-B, and NPR-C receptor-favored ligands are shown by the long black arrows. NPR-C is the most prevalent natriuretic receptor. It largely exists to remove natriuretic peptides from the circulatory system by internalizing and digesting them. The very short bold black lines with a black circle at the end indicate sites on the receptor amino acid sequence of N-linked glycosylation locations outside the cell membrane. Also each partner receptor protein has three disulfide bonds located outside the cell; they are identified by the “R-C-C-R.”

The longitudinal blue ovals that are side-by-side inside the cell each have four phosphorylation sites which are adjacent to the cell membrane. The COOH portion of the GC-A and GC-B receptors (inside the cell) is a green-colored square signifying that the two intracellular portions of the two receptor amino acid strands are covalently linked together. The green box for both receptors is the guanylyl cyclase domain that initiates the production of their biological responses via their second messenger, cGMP. Both the ANP and BNP receptors (1016 amino acid residues) each have full enzymatic activity on their COOH domain (inside the cell). But the NPR-C clearance receptor (~475 amino acid residues) has lost the intracellular amino acid chain of 566 residues and thus has no guanylyl enzymatic activity.

The atrial natriuretic peptide, ANP, is produced, stored, and released mainly by the cardiac myocytes of the heart’s atrium (Figure 1D). A similar system is operative for the release of the “basic” natriuretic peptide (BNP), by the ventricles of the heart. In each instance an elevated vascular volume results in a stretching of the heart’s atrium and ventricles, which initiates the cleavage and secretion, respectively, of both ANP and BNP from the heart. BNP was originally thought to be only secreted by the brain into the circulatory system. More study revealed that BNP was more prevalent in the cardiac ventricles.

The released ANP acts on the kidney (glomeruli) to increase the glomerular filtration rate (GFR) so as to increase renal blood flow which in a short time increases both urine volume (UV) and Na+ excretion (UNa). ANP also decreases plasma renin activity. Natriuresis and diuresis are also enhanced by the sup pression of aldosterone production and its biological actions and by the release from the posterior pituitary of arginine vasopressin (AVP).

The function of the ANPR-C is still emerging. It is widely distributed in the vascular system, but since the ANPR-C has no intracellular domain it therefore has no kinase and guanylylcyclase actions. However, CNP has been shown to both relax the vascular smooth muscle and also is a much stronger dilator of veins than either BNP and ANP. A gene knock-out of CNP was only lethal for one-half of the mice. Intriguingly, the surviving mice had defects in their endochondral bone development and a shortened body length similar to that of human dwarfs.

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مواضيع ذات صلة

Angiotensins I and II

Intragastric Events Leading to Cobalamin Malabsorption

Hormones and Blood Cell Production

Fibroblast Growth Factor-23

Motor Functions of the Intestinal Tract

Control of Renal Magnesium Excretion and Extracellular Magnesium ion Concentration

Regulation of Renal Phosphate Excretion

Control of Calcium Excretion by the Kidneys

Summary of Major Factors That Regulate Potassium Secretion

Overview of Renal Potassium Excretion

Regulation of Internal Potassium Distribution

Production of Steroid Hormones—An Introduction