ROLE OF PHOSPHODIESTERASES IN THE REGULATION OF ENDOTHELIAL PERMEABILITY INVITRO

Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an imp ortant 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 derive d from porcine pulmonary arteries. Effects of H2O2 on endothelial perm eability were completely inhibited by adenylate cyclase activation wit h 10(-12) M cholera toxin or 0.1 muM forskolin. 10(-8) M Sp-cAMPS, a c AMP-dependent protein kinase A agonist, was similarly effective. The p hosphodiesterase (PDE) inhibitors motapizone (10(-4) M), rolipram (10( -6) M), and zardaverine (10(-8) M), which specifically inhibit PDE-iso enzymes III, IV, and III/IV potently blocked H2O2-induced endothelial permeability when combined with 10(-6) M prostaglandin E1. Overall cel lular cAMP content and inhibition of H2O2 effects on endothelial perme ability 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, a nd IV in porcine pulmonary endothelial cells. The data suggest that ad enylate cyclase activation/PDE inhibition is a powerful approach to bl ock H2O2-induced increase in endothelial permeability. This concept ap pears especially valuable when endothelial PDE isoenzyme pattern and P DE inhibitor profile are matched optimally.