Diazenolate-NO-donors like spermine-NONOate use spermine as a nitric oxide releasing carrier. As one of the naturally occurring polyamines, spermine belongs to the most potent platelet aggregation inhibitors among the polyamines. Recent publications describe a dominating role for platelets and nitric oxide in the setting of endothelial dysfunction during endotoxemia. It is unknown whether spermine as single agent, beside his function as nitric oxide releasing carrier, exerts effects on macromolecular leakage during early endotoxemia. In male Wistar rats, macromolecular efflux was determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60 and 120 min after the start of the experiment. In the first part of the experiments we investigated the effects of spermine and spermine-NONOate during leukocyte-independent states of endotoxemia, using the L- and P-selectin inhibitor fucoidin to suppress leukocyte-endothelial-interaction. In the second part we investigated the effects of spermine on endothelial damage during endotoxemia without co-administration of fucoidin. Combined treatment of animals with spermine and fucoidin was as effective as treatment with spermine-NONOate and fucoidin alone. Spermine and fucoidin as single agents had no effects on macromolecular efflux during endotoxin challenge. Combined treatment of animals with spermine and fucoidin reduce macromolecular efflux to the same degree like treatment with spermine-NONOate and fucoidin. A currently unknown interaction between fucoidin and spermine leads to a significant reduction in macromolecular efflux.