Role of nitric oxide and phosphodiesterase isoenzyme II for reduction of endothelial hyperpermeability.
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.
Suttorp
N
N
Department of Internal Medicine, Justus Liebig-University of Giessen, Germany.
Hippenstiel
S
S
Fuhrmann
M
M
Krull
M
M
Podzuweit
T
T
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
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