Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications

Abstract

Natriuretic peptides are a family of three structurally related hormone/ paracrine factors. Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted from the cardiac atria and ventricles, respectively. ANP signals in an endocrine and paracrine manner to decrease blood pressure and cardiac hypertrophy. BNP acts locally to reduce ventricular fibrosis. C-type natriuretic peptide (CNP) primarily stimulates long bone growth but likely serves unappreciated functions as well. ANP and BNP activate the transmembrane guanylyl cyclase, natriuretic peptide receptor-A (NPR-A). CNP activates a related cyclase, natriuretic peptide receptor-B (NPR-B). Both receptors catalyze the synthesis of cGMP, which mediates most known effects of natriuretic peptides. A third natriuretic peptide receptor, natriuretic peptide receptor-C (NPR-C), clears natriuretic peptides from the circulation through receptor-mediated internalization and degradation. However, a signaling function for the receptor has been suggested as well. Targeted disruptions of the genes encoding all natriuretic peptides and their receptors have been generated in mice, which display unique physiologies. A few mutations in these proteins have been reported in humans. Synthetic analogs of ANP (anaritide and carperitide) and BNP (nesiritide) have been investigated as potential therapies for the treatment of decompensated heart failure and other diseases. Anaritide and nesiritide are approved for use in acute decompensated heart failure, but recent studies have cast doubt on their safety and effectiveness. New clinical trials are examining the effect of nesiritide and novel peptides, like CD-NP, on these critical parameters. In this review, the history, structure, function, and clinical applications of natriuretic peptides and their receptors are discussed.

Fig. 1

Structure of the human natriuretic peptides. The structure of the preprohormones for ANP, BNP and CNP are outlined on the left of each panel. The final amino acid sequence and structure of the mature peptides along with the major degradation product are shown on the right. The sites of cleavage are indicated with scissors.

Fig. 2

Sequence alignment of natriuretic peptides. The sequences for the species listed above were obtained from the NCBI Entrez Protein database. The accession numbers for the above sequences (from top to bottom) are: for ANP [NP_006163.1; XP_001141705.1; XP_850357.1; NP_999425.1; NP_999425.1; NP_001075970.1; AAB92564; NP_001075731.1; NP_036744.1; NP_03275.1; P18909; BAA34122; NP_942095], for BNP [NP_002512.1; XP_525186.2; XP_544566.2; P07634; ABG91577; AAB92565; NP_113733.1; NP_032752.1; BAE19674; XP_696498], and for CNP [NP_077720.1; XP_001141992.1; XP_852684.1; NP_001008482.1; XP_001498652; NP_001009479; NP_446202.1; NP_035063.1; BAA04236; BAA13529; XP_692388]. For ANP, the mature circulating form for all mammalian species is 28 amino acid as shown; the same size peptide is shown for the non-mammalian species for comparison purposes only. For BNP, the mature circulating form varies as shown. For CNP, the 53-amino acid form is shown for all.