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To examine this hypothesis, cultured PAEC monolayers were treated with H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>, and barrier function was measured as transmonolayer albumin clearance. H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>caused significant PAEC barrier dysfunction that was attenuated by intracellular as well as extracellular \u00b7NO generation. \u00b7NO increased PAEC cGMP and cAMP levels, but treatment with inhibitors of soluble guanylate cyclase or protein kinase G did not abrogate \u00b7NO-mediated barrier protection. In contrast, H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>decreased protein kinase A activity, and inhibiting protein kinase A abrogated the protective effect of \u00b7NO. H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-induced barrier dysfunction was not associated with decreased levels of cGMP or cAMP. 3-Isobutyl-1-methylxanthine and the cGMP analog 8-bromo-cGMP had little effect on H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>-mediated endothelial barrier dysfunction, whereas 8-bromo-cAMP plus 3-isobutyl-1-methylxanthine was protective. 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