title: Physiological levels of A-, B- and C-type natriuretic peptide shed the endothelial glycocalyx and enhance vascular permeability.
abstract: Atrial natriuretic peptide (ANP) is a peptide hormone released from the cardiac atria during hypervolemia. Though named for its well-known renal effect, ANP has been demonstrated to acutely increase vascular permeability in vivo. Experimentally, this phenomenon was associated with a marked shedding of the endothelial glycocalyx, at least for supraphysiological intravascular concentrations. This study investigates the impact and mechanism of action of physiological doses of ANP and related peptides on the vascular barrier. In isolated guinea pig hearts, prepared and perfused in a modified Langendorff mode with and without the intravascular presence of the colloid hydroxyethyl starch (HES), we measured functional changes in vascular permeability and glycocalyx shedding related to intracoronary infusion of physiological concentrations of A-, B- and C-type natriuretic peptide (ANP, BNP and CNP). Significant coronary venous washout of glycocalyx constituents (syndecan-1 and heparan sulfate) was observed. As tested for ANP, this effect was positively related to the intracoronary concentration. Intravascular shedding of the glycocalyx was morphologically confirmed by electron microscopy. Also, functional vascular barrier competence decreased, as indicated by significant increases in transudate formation and HES extravasation. Ortho-phenanthroline, a non-specific inhibitor of matrix metalloproteases, was able to reduce ANP-induced glycocalyx shedding. These findings suggest participation of natriuretic peptides in pathophysiological processes like heart failure, inflammation or sepsis. Inhibition of metalloproteases might serve as a basis for future therapeutical options.
authors.affiliation: Department of Anesthesiology, University Hospital Munich, Nussbaumstrasse 20, 80336, Munich, Germany. matthias.jacob@med.uni-muenchen.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Jacob
authors.forename: Thomas
authors.initials: T
authors.lastname: Saller
authors.forename: Daniel
authors.initials: D
authors.lastname: Chappell
authors.forename: Markus
authors.initials: M
authors.lastname: Rehm
authors.forename: Ulrich
authors.initials: U
authors.lastname: Welsch
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Becker
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D005122:Exudates and Transudates / Q000378:metabolism; D019276:Glycocalyx / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006168:Guinea Pigs; D006895:Hydroxyethyl Starch Derivatives / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008854:Microscopy, Electron; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism*; D010477:Perfusion; D010618:Phenanthrolines / Q000494:pharmacology; D010952:Plasma Substitutes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D061965:Matrix Metalloproteinase Inhibitors; D010618:Phenanthrolines; D010952:Plasma Substitutes; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; C001635:ferroin; D009320:Atrial Natriuretic Factor; D020782:Matrix Metalloproteinases