Role of phosphodiesterases in the regulation of endothelial permeability in vitro.
Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in the pathogenesis of vascular injury and pulmonary edema. H2O2 time- and dose-dependently increased the hydraulic conductivity and decreased the selectivity of an endothelial cell monolayer derived from porcine pulmonary arteries. Effects of H2O2 on endothelial permeability were completely inhibited by adenylate cyclase activation with 10(-12) M cholera toxin or 0.1 microM forskolin. 10(-8) M Sp-cAMPS, a cAMP-dependent protein kinase A agonist, was similarly effective. The phosphodiesterase (PDE) inhibitors motapizone (10(-4) M), rolipram (10(-6) M), and zardaverine (10(-8) M), which specifically inhibit PDE-isoenzymes III, IV, and III/IV potently blocked H2O2-induced endothelial permeability when combined with 10(-6) M prostaglandin E1. Overall cellular cAMP content and inhibition of H2O2 effects on endothelial permeability were poorly correlated. H2O2 exposure resulted in a rapid and substantial decrease in endothelial cAMP content. The analysis of the PDE isoenzyme spectrum showed high activities of isoenzymes II, III, and IV in porcine pulmonary endothelial cells. The data suggest that adenylate cyclase activation/PDE inhibition is a powerful approach to block H2O2-induced increase in endothelial permeability. This concept appears especially valuable when endothelial PDE isoenzyme pattern and PDE inhibitor profile are matched optimally.
Department of Internal Medicine, Justus Liebig-University, Giessen, Germany.
N
N
Suttorp
U
U
Weber
T
T
Welsch
C
C
Schudt
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects; D000242:Cyclic AMP / Q000032:analysis / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000201:enzymology / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000493:pharmacokinetics; D007527:Isoenzymes / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D011651:Pulmonary Artery; D013552:Swine
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D006861:Hydrogen Peroxide; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases