The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system

Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-ty pe (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure an d increase salt excretion, These functions are mediated by natriuretic pept ide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase d omains that are stimulated when the receptors bind ligand, A more abundantl y expressed receptor (NPRC or C-type) has a short cytoplasmic domain withou t guanylyl cyclase activity. NPRC is thought to act as a clearance receptor , although it may have additional functions, To test how NPRC affects the c ardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [I-125]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, altho ugh plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduc ed ability to concentrate urine, exhibit mild diuresis, and tend to be bloo d volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 13 3 Pa) below normal. These results are consistent with the sole cardiovascul ar/renal function of NPRC being to clear natriuretic peptides, thereby modu lating local effects of the natriuretic peptide system, Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable in crease in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects, W e conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic p eptide system to be tailored to specific local needs.