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Because modification of plasma albumin on tyrosine residues generates nitrated albumin (NOA) that may function as a mechanism of nitrogen monoxide clearance from microcirculation, we investigated biochemicaly and morphologically the cell surface binding and the transendothelial transport of NOA. An electron microscopic study was carried out with mouse lungs and hearts perfused in situ with NOA and NOA-Au complexes. The results indicate that NOA-Au can bind to the endothelial cell surface, and its binding can be blocked by albumin plus nitrotyrosine (NO-tyrosine) or abolished by excess NOA. We detected NOA-Au into perivascular spaces as early as 30 sec after the beginning of its perfusion. NOA, unlike native albumin , leaves the vascular lumina via both endothelial caveolae and open junctions. By cross-linking and ligand blotting analysis, we showed that NOA interacted with the same albumin binding proteins of 16-18, 30-32, 60, and 74 kDa as native albumin. ELISA performed on tissue homogenates obtained from the same specimens showed that NOA transport was 2- to 4-fold greater than native albumin. The augmented transendothelial transport of NOA reflects its transcytosis as well as its exit from the microcirculation via open junctions. The increased transport of NOA may serve as an important mechanism that protects a vascular bed against the damaging effects of nitrogen monoxide and peroxynitrite.

Nitric oxide (N[O.sup.*]) is a short-lived physiological messenger. Its various biological activities can be preserved in a more stable form of S-nitrosothiols (RS-NO). Here we demonstrate that at physiological N[O.sup.*] concentrations, plasma albumin becomes saturated with N[O.sup.*] and accelerates formation of low-molecular-weight (LMW) RS-NO in vitro and in vivo. The mechanism involves micellar catalysis of N[O.sup.*] oxidation in the albumin hydrophobic core and specific transfer of N[O.sup.+] to LMW thiols. Albumin-mediated S-nitrosylation and its vasodilatory effect directly depend on the concentration of circulating LMW thiols. Results suggest that the hydrophobic phase formed by albumin serves as a major reservoir of N[O.sub.*] and its reactive oxides and controls the dynamics of N[O.sup.*]-dependant processes in the vasculature.

Experimental investigations of astrocytes indicate the presence of albumin to cause astrocyte proliferation and calcium spikes in a blood coagulation-independent manner. Albumin, which is a polar lipid influenced by lipase, stimulates DNA synthesis. Reduced levels of albumin attenuate intracellular calcium concentrations. The receptor and signaling pathways of astrocytes vary from those of other cells, as indicated by their differing responses to albumin.

Study of analbuminemia, a rare recessive disorder, leads to the identification of mutations in three unrelated subjects from different countries. In all three cases, a single-nucleotide mutation produces a stop codon, while the mutation occurs at different sites. Size of the putative aborted product of the albumin gene varies from 31-to 213-amino acid residues and there is no experimental evidence for a circulating albumin fragment.