title: The heart communicates with the endothelium through the guanylyl cyclase-A receptor: acute handling of intravascular volume in response to volume expansion.
abstract: Atrial natriuretic peptide (ANP) regulates arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is expressed in vascular endothelium and mediates increases in cGMP, but the functional relevance is controversial. Notably, mice with endothelial-restricted GC-A deletion [EC GC-A knockout (KO) mice] exhibit significant chronic hypervolemic hypertension. The present study aimed to characterize the endothelial effects of ANP and their relevance for the acute regulation of intravascular fluid volume. We studied the effect of ANP on microvascular permeability to fluorescein isothiocyanate-labeled albumin (BSA) using intravital microscopy on mouse dorsal skinfold chambers. Local superfusion of ANP (100 nm) increased microvascular fluorescein isothiocyanate-BSA extravasation in control but not EC GC-A KO mice. Intravenous infusion of synthetic ANP (500 ng/kg x min) caused immediate increases in hematocrit in control mice, indicating intravascular volume contraction. In EC GC-A KO mice, the hematocrit responses were not only abolished but even reversed. Furthermore, acute vascular volume expansion, which caused release of endogenous cardiac ANP, did not affect resting central venous pressure of control mice but rapidly and significantly increased central venous pressure of EC GC-A KO mice. In cultured lung endothelial cells, ANP provoked cGMP-dependent protein kinase I-mediated phosphorylation of vasodilator-stimulated phosphoprotein. We conclude that ANP, via GC-A, enhances microvascular endothelial macromolecule permeability in vivo. This effect might be mediated by cGMP-dependent protein kinase I-dependent phosphorylation of vasodilator-stimulated phosphoprotein. Modulation of transcapillary protein and fluid transport may represent one of the most important hypovolemic actions of ANP.
authors.affiliation: Institutes of Physiology, University of Würzburg, D-97070 Würzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schreier
authors.forename: Sebastian
authors.initials: S
authors.lastname: Börner
authors.forename: Katharina
authors.initials: K
authors.lastname: Völker
authors.forename: Stepan
authors.initials: S
authors.lastname: Gambaryan
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schäfer
authors.forename: Peter
authors.initials: P
authors.lastname: Kuhlencordt
authors.forename: Birgit
authors.initials: B
authors.lastname: Gassner
authors.forename: Michaela
authors.initials: M
authors.lastname: Kuhn
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood / Q000494:pharmacology; D001810:Blood Volume / Q000235:genetics / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology*; D002478:Cells, Cultured; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006400:Hematocrit; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014690:Venous Pressure / Q000235:genetics; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009320:Atrial Natriuretic Factor; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569720:Prkg1 protein, mouse; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A