title: Role of nitric oxide and phosphodiesterase isoenzyme II for reduction of endothelial hyperpermeability.
abstract: Regulation of endothelial permeability is poorly understood. Previous studies have shown that endothelial cells contain phosphodiesterase (PDE) isoenzymes II-IV and that simultaneous adenylate cyclase activation and/or PDE inhibition blocked endothelial hyperpermeability (J.Clin.Invest. 91: 1421-1428, 1993). We now focused on a possible role for guanosine 3',5'-cyclic monophosphate (cGMP)-dependent mechanisms and studied H2O2-exposed porcine pulmonary artery endothelial cell monolayers. Pretreatment of cells with different nitric oxide (NO) donors or atrial natriuretic peptide (ANP) increased endothelial cGMP-content severalfold and blocked H2O2-related effects on permeability; opposite results were obtained with a NO synthase inhibitor. Determination of cGMP degradation in nitroprusside-exposed endothelial cells identified PDE II as the major cGMP metabolizing pathway, whereas PDE III and IV contributed little or nothing. Inhibition of PDE II reduced H2O2-related endothelial hyperpermeability, an effect that could be enhanced synergistically by simultaneous guanylate cyclase activation. In summary, these studies indicate that cGMP-dependent mechanisms (NO donors, ANP, and dibutyryl-cGMP) blocked H2O2-related increases in endothelial permeability. The major cGMP degrading pathway in endothelial cells was PDE II, thereby substituting the missing PDE V in these cells. Simultaneous guanylate cyclase activation and/or PDE II inhibition may be a valuable approach to treat endothelial hyperpermeability.
authors.affiliation: Department of Internal Medicine, Justus Liebig-University of Giessen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Suttorp
authors.forename: S
authors.initials: S
authors.lastname: Hippenstiel
authors.forename: M
authors.initials: M
authors.lastname: Fuhrmann
authors.forename: M
authors.initials: M
authors.lastname: Krull
authors.forename: T
authors.initials: T
authors.lastname: Podzuweit
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004553:Electric Conductivity; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D006460:Hemolysin Proteins / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008981:Molsidomine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D005996:Nitroglycerin / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011651:Pulmonary Artery; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D006460:Hemolysin Proteins; D007527:Isoenzymes; D009599:Nitroprusside; D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D006861:Hydrogen Peroxide; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D005996:Nitroglycerin