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

Vascular Biology Research Group and Department of Physiology and Cell Biology, Albany Medical College, Albany, New York 12208-3479 The present objective was to determine whether hydrogen peroxide (H 2 O 2 ) 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 125 I-labeled albumin clearance ( 125 I-albumin flux/perfusate concentration of 125 I-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 ( ). H 2 O 2 decreased from a control value of 0.93 to 0.38, did not change PS , and increased lung weight. Posttreatment with isoproterenol, a 2 -adrenergic-receptor agonist, reduced the H 2 O 2 -induced decrease in to 0.65 and augmented the increase in lung weight. Posttreatment with CP-80633, a phosphodiesterase 4 inhibitor, further reduced the H 2 O 2 -induced decrease in to 0.79 and blocked the rise in lung weight. In the presence of isoproterenol or CP-80633, H 2 O 2 increased PS . Therefore, H 2 O 2 increased the convective and diffusive clearances of albumin across an intact pulmonary vasculature. Furthermore, inhibition of cAMP metabolism more effectively attenuated the H 2 O 2 -induced increases in convective albumin clearance and lung weight as compared with stimulation of cAMP production. isoproterenol; phosphodiesterase inhibitor; desferrioxamine; iron chelator; permeability-surface area product; reflection coefficient; vascular pressure; vascular resistance; lung weight