Oxidant-increased endothelial permeability: Prevention with phosphodiesterase inhibition vs. cAMP production

The present objective was to determine whether hydrogen peroxide (H₂O₂) increases transvascular albumin clearance and lung weight in an isolated rat lung and whether posttreatment with cAMP-enhancing agents can prevent these increases. Transvascular albumin clearance was assessed by ¹²⁵I-labeled albumin clearance (¹²⁵I-albumin flux/perfusate concentration of ¹²⁵I-albumin) at a given fluid filtration. Nonlinear regression analysis of transvascular albumin clearance vs. fluid filtration yielded values for the permeability-surface area product (PS) and the reflection coefficient (σ), H₂O₂ decreased σ from a control value of 0.93 to 0.38, did not change PS, and increased lung weight. Posttreatment with isoproterenol, a β₂-adrenergic-receptor agonist, reduced the H₂O₂-induced decrease in σ to 0.65 and augmented the increase in lung weight. Posttreatment with CP-80633, a phosphodiesterase 4 inhibitor, further reduced the H₂O₂- induced decrease in σ to 0.79 and blocked the rise in lung weight. In the presence of isoproterenol or CP-80633, H₂O₂ increased PS. Therefore, H₂O₂ increased the convective and diffusive clearances of albumin across an intact pulmonary vasculature. Furthermore, inhibition of cAMP metabolism more effectively attenuated the H₂O₂-induced increases in convective albumin clearance and lung weight as compared with stimulation of cAMP production.