Role of natriuretic peptide clearance receptor in in vivo control of C-type natriuretic peptide

1995 ◽  
Vol 269 (1) ◽  
pp. H326-H331 ◽  
Author(s):  
R. R. Brandt ◽  
D. M. Heublein ◽  
L. L. Aarhus ◽  
J. A. Lewicki ◽  
J. C. Burnett
Keyword(s):  
Natriuretic Peptide ◽  
Clearance Rate ◽  
Metabolic Clearance ◽  
Binding Assays ◽  
Metabolic Clearance Rate ◽  
Amino Acid Peptide ◽  
Cardiovascular Actions ◽  
Clearance Receptor

C-type natriuretic peptide (CNP) is a newly described 22-amino acid peptide of endothelial cell origin, which has selective cardiovascular actions and is structurally related to atrial natriuretic peptide (ANP). Recent in vitro studies have demonstrated that an important regulatory pathway for the clearance of natriuretic peptides involves binding to a common clearance receptor [natriuretic peptide C receptor (NPR-C)]. Although CNP has also been identified as a ligand for NPR-C in binding assays, no studies have defined the in vivo interaction of CNP with NPR-C. CNP (10 ng.kg-1.min-1) followed by C-ANP-(4-23), a specific ligand for NPR-C blockade, was infused intravenously in two groups (both n = 7) of anesthetized dogs at two different doses (0.1 or 1.0 micrograms.kg-1.min-1) to permit calculation of total metabolic clearance rate (TMCR). C-ANP-(4-23) increased circulating CNP and reduced TMCR in both groups. Pulmonary metabolic clearance rate was negative at baseline, suggesting a net secretion of CNP across the lung, which was increased during CNP infusion and was abolished with NPR-C blockade. Renal and femoral metabolic clearance rates were positive at baseline and increased with CNP infusion. A decrease in cardiac output and cardiac filling pressures in response to CNP administration was potentiated by NPR-C blockade. We conclude that 1) circulating CNP achieved by CNP infusion is regulated by NPR-C in vivo, 2) the pulmonary circulation is a possible site of CNP secretion, 3) the renal and peripheral circulations are sites of CNP clearance, and 4) NPR-C blockade potentiates the selective cardiovascular actions of CNP.

Effects of atrial natriuretic peptides on metabolism of arginine vasopressin by isolated perfused rat kidney

1992 ◽  
Vol 263 (2) ◽  
pp. R273-R278
Author(s):  
M. R. Lebowitz ◽  
A. M. Moses ◽  
S. J. Scheinman
Keyword(s):  
Arginine Vasopressin ◽  
Rat Kidney ◽  
Fractional Excretion ◽  
Metabolic Clearance ◽  
Isolated Perfused Rat Kidney ◽  
Perfused Rat Kidney ◽  
Clearance Receptor ◽  
Atrial Natriuretic

Atrial natriuretic peptide (ANP) antagonizes the release and action of arginine vasopressin (AVP) both in vivo and in vitro. We have reported that ANP increases the urinary and metabolic clearances of AVP in normal subjects (A. M. Moses et al. J. Clin. Endocrinol. Metab. 70: 222-229, 1990). To clarify this effect, we perfused isolated rat kidneys in vitro and measured the clearances of AVP for 30 min after the addition of rat ANP [rANP-(1-28), 10(-7) M]. In the perfused kidney, rANP increased the urinary clearance of AVP (UCAVP) from 321 +/- 19 to 417 +/- 20 microliters/min (P less than 0.01) and increased the glomerular filtration rate (GFR) from 558 +/- 28 to 696 +/- 28 microliters/min (P less than 0.01). Fractional excretion of AVP was unchanged. Rates of AVP reabsorption were directly related to filtered AVP, and this relationship was not altered by ANP. ANP did not affect the total organ clearance or the renal metabolic clearance of AVP. The increase in GFR was associated with increases in renal vascular resistance (P less than 0.05), filtration fraction (P less than 0.01), and sodium excretion (P less than 0.001). UCAVP also increased when GFR was raised without ANP by perfusing at higher pressures. The rat ANP clearance receptor agonist [cANP- (4-23), 10(-7) M] did not change GFR or UCAVP. ANP increases UCAVP in the isolated perfused rat kidney. This appears to be a hemodynamic effect of ANP, acting through its biological receptor and not the clearance receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of human pregnancy on metabolic clearance rate of oxytocin

1990 ◽  
Vol 259 (1) ◽  
pp. R21-R24
Author(s):  
S. Thornton ◽  
J. M. Davison ◽  
P. H. Baylis
Keyword(s):  
Clearance Rate ◽  
Late Pregnancy ◽  
High Plasma ◽  
Constant Infusion ◽  
Aminopeptidase Activity ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Human Pregnancy ◽  
In Pregnancy

The metabolic clearance rate (MCR) of oxytocin (OT) was determined by use of constant infusion techniques to achieve low and high plasma OT concentrations in 10 women in late pregnancy and again 8-10 wk postpartum (mean plasma oxytocinase activity was 2.1 IU/ml plasma at term and less than 0.1 IU/ml plasma 8-10 wk postpartum). At the lower plasma OT concentrations (5.0 and 5.2 pg/ml, pregnant and postpartum, respectively) produced by infusion of 17.9 ng/min in pregnancy and 4.3 ng/min postpartum, mean MCR of OT was increased fourfold during pregnancy (5.7 +/- 0.6 and 1.3 +/- 0.1 l/min, pregnant and postpartum, respectively; P less than 0.001). At the higher plasma OT concentrations (8.0 and 8.0 pg/ml, pregnant and postpartum, respectively) produced by infusion of 35.7 ng/min in pregnancy and 8.5 ng/min postpartum, mean MCR of OT was likewise markedly increased during pregnancy compared with postpartum values (7.1 +/- 1.9 and 1.4 +/- 0.1 l/min, respectively; P less than 0.01). The MCR of OT was independent of plasma concentration (between 5 and 8 pg/ml) during pregnancy and in the postpartum period. It is concluded that the MCR of OT is increased markedly during human pregnancy. This may be due to concomitant increases in in vivo cystine aminopeptidase activity or other less specific pregnancy-associated metabolic changes.

scholarly journals In vivo and in vitro degradation of peptide YY3–36 to inactive peptide YY3–34 in humans

2016 ◽  
Vol 310 (9) ◽  
pp. R866-R874 ◽  
Author(s):  
Signe Toräng ◽  
Kirstine Nyvold Bojsen-Møller ◽  
Maria Saur Svane ◽  
Bolette Hartmann ◽  
Mette Marie Rosenkilde ◽  
...  
Keyword(s):  
Half Life ◽  
Peptide Yy ◽  
Degradation Products ◽  
In Vivo Studies ◽  
Metabolic Clearance ◽  
In Vitro Degradation ◽  
Healthy Men ◽  
Amino Acid Peptide

Peptide YY (PYY) is a 36-amino-acid peptide released from enteroendocrine cells upon food intake. The NH2 terminally truncated metabolite, PYY3–36, exerts anorexic effects and has received considerable attention as a possible antiobesity drug target. The kinetics and degradation products of PYY metabolism are not well described. A related peptide, neuropeptide Y, may be degraded from the COOH terminus, and in vivo studies in pigs revealed significant COOH-terminal degradation of PYY. We therefore investigated PYY metabolism in vitro after incubation in human blood and plasma and in vivo after infusion of PYY1–36 and PYY3–36 in eight young, healthy men. A metabolite, corresponding to PYY3–34, was formed after incubation in plasma and blood and during the infusion of PYY. PYY3–34 exhibited no agonistic or antagonistic effects on the Y2 receptor. PYY1–36 infused with and without coadministration of sitagliptin was eliminated with half-lives of 10.1 ± 0.5 and 9.4 ± 0.8 min (means ± SE) and metabolic clearance rates of 15.7 ± 1.5 and 14.1 ± 1.1 ml·kg−1·min−1 after infusion, whereas PYY3–36 was eliminated with a significantly longer half-life of 14.9 ± 1.3 min and a metabolic clearance rate of 9.4 ± 0.6 ml·kg−1·min−1. We conclude that, upon intravenous infusion in healthy men, PYY is inactivated by cleavage of the two COOH-terminal amino acids. In healthy men, PYY3–36 has a longer half-life than PYY1–36.

Abstract 5432: Mutation of Three Amino Acids in the Disulfide-Ring of a CNP Based Chimeric Natriuretic Peptide Alters its Vascular Properties

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Horng H Chen ◽  
Brenda K Huntley ◽  
Candace Y Lee ◽  
Fernando L Martin ◽  
John A Schirger ◽  
...  
Keyword(s):  
Amino Acid ◽  
Natriuretic Peptide ◽  
Right Atrial ◽  
Bolus Administration ◽  
Amino Acid Peptide ◽  
Arterial Blood ◽  
C Terminus ◽  
Cardiac Unloading

BACKGROUND: C-type natriuretic peptide (CNP) is a 22-amino-acid peptide produced mainly in the endothelium with potent cardiac unloading and modest blood pressure lowering actions, but minimal renal actions. Based on our previous knowledge, we recently fused a 6 aa sequence from BNP to the C-terminus and a 5 aa sequence from ANP to the N-terminus of CNP. This novel hybrid peptide, CBA-NP, has cardiac unloading actions and mild hypotensive effects similar to CNP. Importantly however, the N and C terminus alterations resulted in potent renal excretory actions. here we test the hypothesis that the 3 aa GSM 15–17 in the disulfide-ring mediate the vascular and hypotensive actions. We therefore mutated GSM 15–17 to REA 15–17 , which we named ABC-NP and compared its in vivo and in vitro actions to CBA-NP. METHODS: We determined the cardiorenal and humoral actions of intravenous bolus administration of CBA-NP (n=5) and ABC-NP (n=5) at 25 microgram/Kg in 2 separate group of normal anesthetized dogs. We also assessed the cGMP response of both peptides in human aortic endothelial cells (HAEC), human cardiac fibroblast (HCF) and isolated canine glomeruli. * p<0.05 RESULTS: IV bolus administration of CBA-NP and ABC-NP resulted in diuresis* and natriuresis*. There was a significant decrease in mean arterial blood (MAP) pressure with CBA-NP (126±6 to113±7 mmHg*) but no change with ABC-NP(126±8 to126±8 mmHg) . In addition, the reduction in pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP) was significantly greater with CBA-NP as compared to ABC-NP. cGMP generation in HAEC and HCF was minimal with ABC-NP and was significantly higher with CBA-NP*. In contrast, cGMP generation was similar in isolated glomeruli between the two peptides. CONCLUSION: Our studies demonstrates that mutation of three amino acid (aa) residues within the CNP ring of CBA-NP from GSM 15–17 to REA alters the vascular but not the renal excretory properties. Hence by this strategic mutation within the ring of CBA-NP, we have designed a renal specific peptide ABC-NP resulting in new sequence specific functional information which can be used to design organ specific therapeutic peptides with unique properties tailored for a specific disease state.

In vitro metabolism of progestins. III. The metabolic clearance rate of medroxyprogesterone acetate in monkeys

Steroids ◽  
1977 ◽  
Vol 29 (3) ◽  
pp. 399-406 ◽  
Author(s):  
Neal A. Musto ◽  
David Nahrwold ◽  
Momčilo Miljković ◽  
C.Wayne Bardin
Keyword(s):  
Medroxyprogesterone Acetate ◽  
Clearance Rate ◽  
In Vitro Metabolism ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate

Metabolism of pure human erythropoietin in the rat

1984 ◽  
Vol 247 (1) ◽  
pp. F168-F176 ◽  
Author(s):  
D. S. Emmanouel ◽  
E. Goldwasser ◽  
A. I. Katz
Keyword(s):  
Clearance Rate ◽  
Gel Filtration ◽  
Kidney Tissue ◽  
Molecular Size ◽  
Constant Infusion ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Concentration Difference ◽  
Human Erythropoietin

The metabolism of pure human erythropoietin (EPO) labeled with 125I was studied in the rat. Concentrations of the labeled hormone (125I-EPO) in plasma and urine were measured by both trichloroacetic acid precipitation and gel filtration. During steady-state conditions the metabolic clearance rate of 125I-EPO was slow, averaging 256 +/- 7 microliter. min-1 X kg-1 of which only 19 +/- 2 microliter X min-1 X kg-1 (or 7.4 +/- 0.8% of the metabolic clearance rate) could be accounted for by excretion of the labeled hormone in the urine. Urinary clearance of 125I-EPO amounted to less than 0.3% of the glomerular filtration rate, and there was no detectable arteriovenous concentration difference of 125I-EPO across the kidney. After both pulse injection and constant infusion to equilibrium, disappearance of 125I-EPO from the circulation could be approximated by a single exponential function: plasma half-life was 3.5 +/- 0.2 h in normal rats and was prolonged to 4.4 +/- 0.3 h (P less than 0.05) in animals with ligated renal pedicles. Although kidney homogenates degraded 125I-EPO in vitro (optimum pH 4.5), the hormone did not accumulate in the kidney when injected intravenously. We conclude that EPO metabolism is extremely sluggish compared with that of other polypeptide hormones. Whereas kidney tissue is capable of degrading EPO in vitro, the physicochemical characteristics of this glycoprotein (molecular size, shape, and charge) probably impede its access to degrading sites and therefore account for the limited contribution of renal extraction and excretion to the metabolic clearance of the hormone.

Renal catabolism of human glucagon-like peptides 1 and 2

1990 ◽  
Vol 68 (12) ◽  
pp. 1568-1573 ◽  
Author(s):  
Carmen Ruiz-Grande ◽  
José Pintado ◽  
Cristina Alarcón ◽  
Carlos Castilla ◽  
Isabel Valverde ◽  
...  
Keyword(s):  
Glomerular Filtration ◽  
Clearance Rate ◽  
Rat Kidney ◽  
In Vivo Studies ◽  
Metabolic Clearance ◽  
Isolated Kidney ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The renal catabolism of [125I]glucagon-like peptide 1 (GLP-1) and [125I]glucagon-like peptide 2 (GLP-2) has been studied both in vivo, by the disappearance of these peptides from the plasma of bilaterally nephrectomized (BNX), ureteral-ligated (BUL) or normal rats, and in vitro, analyzing their catabolism by the isolated, perfused rat kidney. Results from in vivo studies demonstrated that half-disappearance time for both peptides was lower in controls than in BUL rats, and this value in BUL rats was not significantly different from that in BNX rats. In addition, metabolic clearance rate of GLP-1 was higher in control rats than in the other two groups of animals. Urinary clearance rate of both peptides was negligible. In isolated kidney experiments, values for organ clearance of both [125I]GLP-1 and [125I]GLP-2 were similar to those of inulin clearance, which represents the glomerular filtration rate. Urinary clearance of trichloroacetic acid precipitable radioactivity represented less than 1% of total clearance. In conclusion, these results demonstrate a significant role for the kidney in the plasma removal of [125I]GLP-1 and [125I]GLP-2 by a mechanism that involves glomerular filtration and tubular catabolism.Key words: protein catabolism, gastrointestinal peptides, isolated kidney, renal failure.

Evidence suggesting that cadmium induces a non-thyroidal illness syndrome in the rat

1997 ◽  
Vol 154 (1) ◽  
pp. 113-117 ◽  
Author(s):  
M A Pavia ◽  
B Paier ◽  
M I Noli ◽  
K Hagmüller ◽  
A A Zaninovich
Keyword(s):  
Body Weight ◽  
Wistar Rats ◽  
Turnover Rate ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Normal Response ◽  
Stimulation Of ◽  
Fractional Turnover

Abstract The effect of in vivo administration of cadmium chloride on the pituitary-thyroidal axis was assessed in 200 g body weight Wistar rats. A dose of 2·5 mg/kg body weight was injected i.v. 24 h before the experiments were initiated. Plasma thyroxine (T4) and tri-iodothyronine (T3) concentrations in cadmium-treated rats were significantly (P<0·01) decreased, whereas plasma TSH failed to increase in response to low T4 and T3. However, the TSH response to TRH and the pituitary content of TSH in these rats were both normal. Cadmium induced a significant (P<0·01) decrease in 4-h thyroidal 131I uptake and in thyroid/plasma radioactivity ratio. The in vitro conversion of T4 to T3 in the pituitary was significantly (P<0·01) blocked by cadmium whereas there was no in vivo effect. Parameters of peripheral T4 kinetics in cadmium-treated rats, such as metabolic clearance rate (P<0·01), fractional turnover rate (P<0·01), absolute disposal rate (P<0·05), urinary clearance (P<0·05) and faecal clearance (P<0·05), were all decreased by cadmium. The lack of response of TSH to low plasma T4 and T3 and the normal response to exogenous TRH in this and in other non-thyroidal illness syndromes produced by other pathologies suggest a decreased stimulation of pituitary thyrotrophs by endogenous TRH. Journal of Endocrinology (1997) 154, 113–117

scholarly journals Competitive binding of musclin to natriuretic peptide receptor 3 with atrial natriuretic peptide

2009 ◽  
Vol 201 (2) ◽  
pp. 287-295 ◽  
Author(s):  
Shunbun Kita ◽  
Hitoshi Nishizawa ◽  
Yosuke Okuno ◽  
Masaki Tanaka ◽  
Atsutaka Yasui ◽  
...  
Keyword(s):  
Atrial Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Homologous Region ◽  
Binding Assays ◽  
Peptide Receptor ◽  
High Affinity ◽  
Clearance Receptor ◽  
Competitive Nature ◽  
Atrial Natriuretic

Musclin is a novel skeletal muscle-derived secretory factor that was isolated by our group. Musclin contains a region homologous to natriuretic peptides (NPs). This study investigated the interaction between musclin and NP receptors (NPRs). Musclin specifically bound to NPR3, but not to NPR1 or NPR2. Musclin and atrial natriuretic peptide (ANP) competed for binding to NPR3. We conducted binding assays using various synthetic musclin peptides and mutant musclin proteins. The first NP-homologous region in musclin (88LDRL91) and the second homologous region (117MDRI120) were responsible cooperatively for high-affinity binding to NPR3. The first NP-homologous region was more importantly associated with binding to NPR3, than the second homologous region. The competitive nature of musclin with ANP for the natriuretic clearance receptor NPR3 was also confirmed in vivo. We conclude that musclin binds to NPR3 competitively with ANP and may affect ANP concentrations in a local or systemic manner.

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