Role of phosphodiesterases in the regulation of endothelial permeability in vitro.

Abstract

Neutrophil-derived hydrogen peroxide (H202) is believed to play an important role in the pathogenesis of vascular injury and pulmonary edema. H202 time-and dose-dependently increased the hydraulic conductivity and decreased the selectivity of an endothelial cell monolayer derived from porcine pulmonary arteries. Effects of H202 on endothelial permeability were completely inhibited by adenylate cyclase activation with 10-12 M cholera toxin or 0.1 juM forskolin. 10' M Sp-cAMPS, a cAMP-dependent protein kinase A agonist, was similarly effective. The phosphodiesterase (PDE) inhibitors motapizone (10'-M), rolipram (10-' M), and zardaverine (10-8 M), which specifically inhibit PDE-isoenzymes III, IV, and III/IV potently blocked H202-induced endothelial permeability when combined with 10' M prostaglandin El. Overall cellular cAMP content and inhibition of H202 effects on endothelial permeability were poorly correlated. H202 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 H202-induced increase in endothelial permeability. This concept appears especially valuable when endothelial PDE isoenzyme pattern and PDE inhibitor profile are matched optimally. (J.

Acute versus chronic administration of phosphodiesterase inhibitors on allergen‐induced pulmonary cell influx in sensitized guinea‐pigs

“…Finally, it is also possible that PDE inhibitors may be affecting the permeability of endothelial cells. Type III and IV inhibitors have been shown to reduce endothelial cell permeability in vitro (Seiburt et al, 1992;Suttorp et al, 1993) and it has been demonstrated in vivo that rolipram can inhibit PAF-induced plasma extravasation in guinea-pig airways (Raeburn & Karlsson, 1992).…”

Adrenomedullin Reduces Endothelial Hyperpermeability

“…5,9,11 Exposure of endothelial cells to hydrogen peroxide (H 2 O 2 ) results in the activation of multiple signaling pathways, finally leading to the activation of myosin light chain (MLC) kinase and disrupted barrier function. 7,8 Thrombin-activated Rho kinase increases the phosphorylation of endothelial cell MLC by directly phosphorylating MLC and simultaneously inhibiting MLC phosphatase, thereby maximally enhancing MLC phosphorylation. 4,5 The hemolysin of Escherichia coli (HlyA) is an important prototype of pore-forming bacterial exotoxins that allows Ca 2ϩ influx into the cytosol of target cells.…”

“…2,8,9,14 Analysis of the endothelial cell PDE isoenzyme pattern showed high activities of PDE2 to PDE4. PDE2 mainly metabolizes cGMP, whereas PDE3/4 is specific for cAMP.…”

“…Activation of cell contraction and disturbance of junctional organization subsequently result in the induction of interendothelial gaps followed by enhanced paracellular endothelial permeability. [2][3][4][5][6] Major initiators of this process are polymorphonuclear leukocyte-derived oxygen metabolites, [7][8][9] pore-forming bacterial exotoxins, 9,10 and endogenous proinflammatory mediators, such as thrombin. 5,9,11 Exposure of endothelial cells to hydrogen peroxide (H 2 O 2 ) results in the activation of multiple signaling pathways, finally leading to the activation of myosin light chain (MLC) kinase and disrupted barrier function.…”

Modelo experimental de perfusão pulmonar ex vivo em ratos: avaliação de desempenho de pulmões submetidos à administração de prostaciclina inalada versus parenteral

“…(14,15) Prostaglandins, such as PGE 1 and PGI 2 , are potent vasodilators that are generally administered directly to the pulmonary circulation at the time of graft perfusion and are added to the hypothermic preservation solution. The beneficial effect of prostaglandins on lung transplantation is related to the preservation of the endothelial barrier of the pulmonary vasculature (16) and to vasodilation, which facilitates the distribution of the preservation solution through the lung parenchyma at extraction. Intracellular solutions, such as the Euro-Collins and University of Wisconsin solutions, have a high potassium content, which causes pulmonary vasoconstriction, vasodilators being therefore required during the administrations of such solutions.…”