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Matsukawa N, Grzesik WJ, Takahashi N, et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system

Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 07/1999; 96(13). DOI: 10.1073/pnas.96.13.7403
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ABSTRACT Natriuretic peptides (NPs), mainly produced in heart [atrial (ANP) and B-type (BNP)], brain (CNP), and kidney (urodilatin), decrease blood pressure and increase salt excretion. These functions are mediated by natriuretic peptide receptors A and B (NPRA and NPRB) having cytoplasmic guanylyl cyclase domains that are stimulated when the receptors bind ligand. A more abundantly expressed receptor (NPRC or C-type) has a short cytoplasmic domain without guanylyl cyclase activity. NPRC is thought to act as a clearance receptor, although it may have additional functions. To test how NPRC affects the cardiovascular and renal systems, we inactivated its gene (Npr3) in mice by homologous recombination. The half life of [125I]ANP in the circulation of homozygotes lacking NPRC is two-thirds longer than in the wild type, although plasma levels of ANP and BNP in heterozygotes and homozygotes are close to the wild type. Heterozygotes and homozygotes have a progressively reduced ability to concentrate urine, exhibit mild diuresis, and tend to be blood volume depleted. Blood pressure in the homozygotes is 8 mmHg (1 mmHg = 133 Pa) below normal. These results are consistent with the sole cardiovascular/renal function of NPRC being to clear natriuretic peptides, thereby modulating local effects of the natriuretic peptide system. Unexpectedly, Npr3 -/- homozygotes have skeletal deformities associated with a considerable increase in bone turnover. The phenotype is consistent with the bone function of NPRC being to clear locally synthesized CNP and modulate its effects. We conclude that NPRC modulates the availability of the natriuretic peptides at their target organs, thereby allowing the activity of the natriuretic peptide system to be tailored to specific local needs

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Available from: Stephen C Pang, May 13, 2014
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    • "The second class of NP receptors is termed NPRB and conversely preferentially binds to CNP, but with lesser affinity to ANP and BNP. The third, NPRC is an interesting receptor as its role is to clear circulating NPs, especially ANP (Anand-Srivastava, 2005) thereby in this unique manner controlling NP interactions with its receptors at its site of action (Matsukawa et al., 1999). "
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    ABSTRACT: White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS-norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation. WAT sympathetic drive is appropriately measured by electrophysiological and neurochemical (NE turnover) in non-human animals and this drive is fat pad-specific preventing generalizations among WAT depots and non-WAT organs. Leptin-triggered SNS-mediated lipolysis is weakly supported, whereas insulin or adenosine inhibition of SNS/NE-mediated lipolysis is strongly supported. In addition to lipolysis control, increases or decreases in WAT SNS drive/NE inhibit and stimulate white adipocyte proliferation, respectively. WAT sensory nerves are of spinal-origin and sensitive to local leptin and increases in sympathetic drive, the latter implicating lipolysis. Transsynaptic viral tract tracer use revealed WAT central sympathetic and sensory circuits including SNS-sensory feedback loops that may control lipolysis.
    Frontiers in Neuroendocrinology 04/2014; 35(4). DOI:10.1016/j.yfrne.2014.04.001 · 7.58 Impact Factor
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    • "The second class of NP receptors is termed NPRB and conversely preferentially binds to CNP, but with lesser affinity to ANP and BNP. The third, NPRC is an interesting receptor as its role is to clear circulating NPs, especially ANP (Anand-Srivastava, 2005) thereby in this unique manner controlling NP interactions with its receptors at its site of action (Matsukawa et al., 1999). "
    [Show abstract] [Hide abstract]
    ABSTRACT: White adipose tissue (WAT) is innervated by the sympathetic nervous system (SNS) and its activation is necessary for lipolysis. WAT parasympathetic innervation is not supported. Fully-executed SNS-norepinephrine (NE)-mediated WAT lipolysis is dependent on β-adrenoceptor stimulation ultimately hinging on hormone sensitive lipase and perilipin A phosphorylation. WAT sympathetic drive is appropriately measured by electrophysiological and neurochemical (NE turnover) in non-human animals and this drive is fat pad-specific preventing generalizations among WAT depots and non-WAT organs. Leptin-triggered SNS-mediated lipolysis is weakly supported, whereas insulin or adenosine inhibition of SNS/NE-mediated lipolysis is strongly supported. In addition to lipolysis control, increases or decreases in WAT SNS drive/NE inhibit and stimulate white adipocyte proliferation, respectively. WAT sensory nerves are of spinal-origin and sensitive to local leptin and increases in sympathetic drive, the latter implicating lipolysis. Transsynaptic viral tract tracer use revealed WAT central sympathetic and sensory circuits including SNS-sensory feedback loops that may control lipolysis.
    Frontiers in Neuroendocrinology 01/2014; · 7.58 Impact Factor
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    • "Studies conducted in intestinal smooth muscle cells (SMCs) suggested that this receptor may also participate in mediating some of the cellular actions of NPs by means of coupling to G i proteins and negative modulation of adenylyl cyclase activity (Murthy et al., 2000). However, the hypotensive and hypovolaemic phenotype of mice with ablated NPR-C indicates that at least within the cardiovascular system this receptor mainly functions to regulate circulating and local NP concentrations (Matsukawa et al., 1999). A third 'natriuretic' peptide, C-type NP (CNP), acting via its GC-B receptor (also known as NPR-B), probably is not involved in body fluid control and blood pressure, at least under physiological conditions. "
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    ABSTRACT: The cardiac hormone atrial natriuretic peptide (ANP) is critically involved in the maintenance of arterial blood pressure and intravascular volume homeostasis. Its cGMP-producing GC-A receptor is densely expressed in the microvascular endothelium of the lung and systemic circulation, but the functional relevance is controversial. Some studies reported that ANP stimulates endothelial cell permeability, whereas others described that the peptide attenuates endothelial barrier dysfunction provoked by inflammatory agents such as thrombin or histamine. Many studies in vitro addressed the effects of ANP on endothelial proliferation and migration. Again, both pro- and anti-angiogenic properties were described. To unravel the role of the endothelial actions of ANP in vivo, we inactivated the murine GC-A gene selectively in endothelial cells by homologous loxP/Cre-mediated recombination. Our studies in these mice indicate that ANP, via endothelial GC-A, increases endothelial albumin permeability in the microcirculation of the skin and skeletal muscle. This effect is critically involved in the endocrine hypovolaemic, hypotensive actions of the cardiac hormone. On the other hand the homologous GC-A-activating B-type NP (BNP), which is produced by cardiac myocytes and many other cell types in response to stressors such as hypoxia, possibly exerts more paracrine than endocrine actions. For instance, within the ischaemic skeletal muscle BNP released from activated satellite cells can improve the regeneration of neighbouring endothelia. This review will focus on recent advancements in our understanding of endothelial NP/GC-A signalling in the pulmonary versus systemic circulation. It will discuss possible mechanisms accounting for the discrepant observations made for the endothelial actions of this hormone-receptor system and distinguish between (patho)physiological and pharmacological actions. Lastly it will emphasize the potential therapeutical implications derived from the actions of NPs on endothelial permeability and regeneration.
    British Journal of Pharmacology 01/2012; 166(2):522-31. DOI:10.1111/j.1476-5381.2012.01827.x · 4.99 Impact Factor
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