INHIBITION OF NITRIC-OXIDE PRODUCTION - MECHANISMS OF VASCULAR ALBUMIN LEAKAGE

The mechanisms by which nitric oxide modulates microvascular albumin e xchange were investigated by monitoring leukocyte-endothelial cell adh esion and fluorescein isothiocyanate-albumin leakage in rat mesenteric venules exposed to N(G)-nitro-L-arginine methyl ester (L-NAME). L-NAM E elicited an initial rapid increase followed by a slower rate of albu min accumulation in the interstitial space. The initial phase of album in leakage preceded the L-NAME-induced leukocyte adherence and emigrat ion, whereas the magnitude of the albumin leakage observed in the late r phase of L-NAME exposure was highly correlated with the number of ad herent and emigrated leukocytes in the same segment of venule. Monoclo nal antibodies (MAbs) directed against adhesion molecules CD11/CD18, I CAM-1, or P-selectin, but not a nonbinding MAb, attenuated the albumin leakage induced by L-NAME. WEB2086, a platelet activating factor anta gonist, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) re duced the leukocyte adherence and emigration as well as the increased albumin leakage. Only 8-br-cGMP and the P-selectin MAb attenuated the platelet-leukocyte aggregation elicited by L-NAME. Phalloidin, which p romotes endothelial junctional integrity, inhibited both the early and late phases of albumin leakage. Overall, these findings suggest that the increased albumin leakage observed in postcapillary venules after inhibition of nitric oxide production involves a mechanism that includ es a role for cGMP, platelet activating factor, leukocyte-endothelial cell adhesion, and the endothelial cell cytoskeleton.