ENDOTHELIAL BARRIER DYSFUNCTION AND OXIDATIVE STRESS - ROLES FOR NITRIC-OXIDE

Endothelial dysfunction has an important role to play in the pathophys iology of human vascular disease. The maintenance of barrier function is critical to the role of vascular endothelium in cardiovascular haem ostasis and this function can be compromised by inflammatory mediators , cytokines or oxidants. Under conditions of oxidative stress a variet y of reactive oxygen species (ROS) may be generated, which increase th e permeability of the endothelial monolayer to fluid, macromolecules a nd inflammatory cells. The endothelium-derived nitric oxide radical (N O), whose physiological actions include effects on vascular smooth mus cle, is normally inactivated by the superoxide radical anion. While la rge amounts of NO have cytotoxic potential, it is now becoming clear t hat combinations of NO with ROS can produce either cytotoxic or cytopr otective effects, depending on the relative amounts of each which are present in the target cell or its environment at a particular time. Th e contribution of NO to oxidant-mediated endothelial barrier dysfuncti on can be assessed in vitro in endothelial monolayers grown on porous membrane supports. In this model, using hydrogen peroxide (H2O2) as th e oxidant, H2O2-induced losses of barrier function can be enhanced or partially offset by NO donor drugs, depending on the concentration of NO donor used. Furthermore, the injurious or cytoprotective effects of these agents appear to be determined by the quantity of NO generated. Since NO is administered clinically by inhalation in conditions such as pulmonary hypertension or the adult respiratory distress syndrome, which are themselves associated with generation of ROS, it is likely t hat low concentrations of NO may protect the pulmonary vascular endoth elium while high concentrations might be expected to combine with ROS to yield intermediates capable of causing further endothelial injury o r loss of barrrier function.