title: Opposing effects of ATP and adenosine on barrier function of rat coronary microvasculature.
abstract: ATP can differentially affect the micro- and macrovascular endothelial barrier. It has been shown that it can both increase and/or decrease macromolecule permeability of microvascular endothelial cells and microvessels, in vivo. We hypothesised that the barrier stabilising effect is mediated by ATP itself via P2 receptors, while barrier-disrupting effect is mediated by its metabolite adenosine via adenosine receptors. The effects of ATP, ADP, AMP and adenosine on barrier function were studied in cultured rat coronary microvascular endothelial monolayers (RCEC) in vitro, as well as in rat mesentery vessels, and in rat hearts in vivo. ATP and ADP showed a biphasic effect on permeability of RCEC monolayers with a reduction followed by a later increase in albumin permeability. The permeability decreasing effect of ATP was enhanced by ecto-nucleotidase inhibitor ARL67156 while permeability increasing effect was enhanced by apyrase, an extracellular ecto-nucleotidase. Moreover, the permeability increasing effect was abrogated by adenosine receptor antagonists, 8-phenyltheophylline (8-PT) and DMPX. Adenosine and adenosine receptor agonists 5'-(N-ethylcarboxamido)-adenosine (NECA), CGS21680, and R-PIA enhanced albumin permeability which was antagonised by 8-PT, A(1), and A(2) but not by A(3) receptor antagonists. Likewise, immunofluorescence microscopy of VE-cadherin and actin showed that NECA induces a disturbance of intercellular junctions. Pre-incubation of ATP antagonised the effects of NECA on permeability, actin cytoskeleton and intercellular junctions. Similar effects of the applied substances were observed in rat mesentery artery by determining the vascular leakage using intravital microscopy as well as in rat hearts by assessing myocardial water contents in vivo. In conclusion, the study demonstrates that in RCEC, ATP, ADP, and its metabolite adenosine play opposing roles on endothelial barrier function.
authors.affiliation: Zentrum für Innere Medizin, Abteilung Kardiologie/Angiologie, Universitätsklinikum Giessen und Marburg, Geissen, Germany. dursun.guenduez@med.uni-giessen.de
authors.forename: Dursun
authors.initials: D
authors.lastname: Gündüz
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.forename: Uwe
authors.initials: U
authors.lastname: Krieger
authors.forename: Lutz
authors.initials: L
authors.lastname: Becker
authors.forename: Mathias
authors.initials: M
authors.lastname: Grebe
authors.forename: Muhammad
authors.initials: M
authors.lastname: Arshad
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Sedding
authors.forename: Frauke V
authors.initials: FV
authors.lastname: Härtel
authors.forename: Yaser
authors.initials: Y
authors.lastname: Abdallah
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Piper
authors.forename: Reinhard K
authors.initials: RK
authors.lastname: Voss
authors.forename: Thomas
authors.initials: T
authors.lastname: Noll
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000241:Adenosine / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D004489:Edema, Cardiac / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D008297:Male; D009206:Myocardium; D010539:Permeability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D058906:Purinergic P1 Receptor Agonists / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014699:Venules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D015820:Cadherins; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D058919:Purinergic P2 Receptor Antagonists; D018047:Receptors, Purinergic P1; D019830:Adenosine-5'-(N-ethylcarboxamide); D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D013806:Theophylline; C028322:8-phenyltheophylline; D000241:Adenosine