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Laura L Swystun, David Lillicrap Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON, CanadaCorrespondence: David Lillicrap, Richardson Laboratory, Queen’s University, 88 Stuart Street, Kingston, Ontario, K7L 3N6, Canada, Tel +1 613 548-1304, Fax +1 613 548-1356, Email david.lillicrap@queensu.caAbstract: The inherited bleeding disorder hemophilia A involves the quantitative deficiency of the coagulation cofactor factor VIII (FVIII). Prophylactic treatment of severe hemophilia A patients with FVIII concentrates aims to reduce the frequency of spontaneous joint bleeding and requires personalized tailoring of dosing regimens to account for the substantial inter-individual variability of FVIII pharmacokinetics. The strong reproducibility of FVIII pharmacokinetic (PK) metrics between repeat analyses in the same individual suggests this trait is genetically regulated. While the influence of plasma von Willebrand factor antigen (VWF:Ag) levels, ABO blood group, and patient age on FVIII PK is well established, estimates suggest these factors account for less than 35% of the overall variability in FVIII PK. More recent studies have identified genetic determinants that modify FVIII clearance or half-life including VWF gene variants that impair VWF-FVIII binding resulting in the accelerated clearance of VWF-free FVIII. Additionally, variants in receptors that regulate the clearance of FVIII or the VWF-FVIII complex have been associated with FVIII PK. The characterization of genetic modifiers of FVIII PK will provide mechanistic insight into a subject of clinical significance and support the development of personalized treatment plans for patients with hemophilia A.Keywords: factor VIII, hemophilia A, von Willebrand factor, pharmacokinetics, clearance receptor

Background: Three specific receptors for the cardiac natriuretic peptide system have been identified to date. Down-regulation of the biologically active binding sites (i.e. NPR-A and NPR-B) could explain the blunted response to cardiac natriuretic hormones observed in heart failure (HF), but not the increased metabolic clearance rate. Variations in the ratio between biological and clearance (NPR-C) receptors in target tissue may explain this increase.Aim: The aim of this study was to investigate the regulation of NPR-C receptors on platelets, in patients with HF.Methods: Eighteen patients with HF (NYHA class: I-II, n=8; III-IV, n=10) and 18 age-matched healthy subjects were studied. The affinity constant (K(d)) and density (B(max)) of binding sites were derived by saturation assays on platelet suspensions using 125I-ANP as radioligand.Results: B(max) increased as a function of the severity of disease: 21.3+/-3.3 fmol/10(9) cells in class III-IV, 11.7+/-2.2 in class I-II, and 11.6+/-1.1 in controls, respectively (P=0.0179 for class III-IV vs. controls and P=0.0451 vs. NYHA I-II).Conclusions: The increase in density of 'clearance' receptors in severe HF is theoretically consistent with the reduction in cardiac natriuretic peptide biological activity, as well as the increase in metabolic clearance rate. This suggests that clearance receptor blockade may be of potential therapeutic value in HF. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate myocardial mRNA expression of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in different regions of the heart at three different time points after induction of myocardial infarction (MI) in rats. Furthermore, we examined putative changes in mRNA expression of natriuretic peptide receptors (NPRs), NPR-A and NPR-C, in myocardium and peripheral organs. Substantial increase in the mRNA levels of both BNP and ANP in the infarcted as well as non-infarcted regions were observed after induction of MI. These findings were paralleled by elevated circulating concentrations of ANP, BNP and N-terminal proANP (Nt-proANP). In addition, the mRNA levels of the clearance receptor, NPR-C, were augmented in the infarcted and non-infarcted regions of the left ventricular wall (LV), while it was decreased in the kidneys and lungs 28 days post-MI. Based on these data, we propose that, in addition to increased myocardial secretion of BNP and ANP, reduced peripheral clearance by NPR-C may contribute to the observed increase in circulating plasma concentrations of the natriuretic peptides after induction of MI in rats. [ABSTRACT FROM AUTHOR]

To assess clearance mechanisms of atrial and brain natriuretic peptides in the circulation, we examined the effects of a neutral endopeptidase (NEP) inhibitor and a clearance receptor ligand on plasma concentrations of the peptides in normal rats. Plasma concentrations of endogenous α-rat atrial natriuretic peptide (α-rANP) were not significantly elevated by intravenous infusion of a NEP inhibitor, phosphoramidon, but were elevated threefold by intravenous infusion of a clearance receptor ligand, des(Gln-Gly)-rANP-NH [C-ANF]. On the other hand, the clearance of α-rANP given intravenously at the pharmacological dose, 600 pmol/ min/kg for 2 min, was decreased to one-third by the administration of phosphoramidon, although the administration of C-ANF did not significantly decrease the clearance. The clearance of rat brain natriuretic peptide (rBNP) given at 600 pmol/min/kg for 2 min was approximately 38% lower than that of α-rANP. The effect of phosphoramidon on the clearance of rBNP was not significant and was similar to that of C-ANF. These results suggest that clearance receptor is involved in the clearance of the physiological levels of α-rANP and that NEP plays a major role in the clearance of a pharmacological dose of α-rANP, at which clearance receptors are thought to be saturated, and also indicate a pharmacokinetic difference between α-rANP and rBNP. [ABSTRACT FROM AUTHOR]

The natriuretic peptide family consists of three biologically active peptides: atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). ANP and BNP, secreted by the heart, act as cardiac hormones, whereas CNP is an endothelial peptide. The aim of this manuscript is to review the production, action mechanisms, effects and clinical applications of natriuretic peptides., (Copyright © 2021. Published by Elsevier Masson SAS.)